Anti-cd39 antibodies, compositions comprising anti-cd39 antibodies and methods of using anti-cd39 antibodies

ABSTRACT

Provided herein are antibodies that selectively bind to CD39 and its isoforms and homologs, and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as therapeutic and diagnostic methods.

RELATED APPLICATION

This application claims priority to U.S. provisional application No.62/539,527, filed Jul. 31, 2017, which is incorporated by referenceherein in its entirety.

FIELD

Provided herein are antibodies with binding specificity for CD39 andcompositions comprising the antibodies, including pharmaceuticalcompositions, diagnostic compositions and kits. Also provided aremethods of using anti-CD39 antibodies for therapeutic and diagnosticpurposes.

BACKGROUND

CD39 is an integral membrane protein that phosphohydrolyzes ATP to yieldADP and AMP. Human CD39 is a 510-amino acid protein with seven potentialN-linked glycosylation sites, 11 cysteine residues, and twotransmembrane regions. Structurally, it is characterized by twotransmembrane domains, a small cytoplasmic domain comprising the NH₂-and COOH-terminal segments, and a large extracellular hydrophobic domainconsisting of five highly conserved domains, known as apyrase conservedregions (ACR) 1-5, which are pivotal for the catabolic activity of theenzyme. CD39 becomes catalytically active upon its localization on thecell surface, and its glycosylation is important for protein folding,membrane targeting, and enzyme activity.

CD39 is constitutively expressed in spleen, thymus, lung, and placentaand in these tissues it is associated primarily with endothelial cellsand immune cell populations, such as B cells, natural killer (NK) cells,dendritic cells, Langerhans cells, monocytes, macrophages, mesangialcells, neutrophils, and regulatory T cells (Tregs). Given that CD39,along with other enzymes, degrades ATP, ADP, and AMP to adenosine, CD39can be viewed as an immunological switch that shifts ATP-drivenpro-inflammatory immune cell activity toward an anti-inflammatory statemediated by adenosine.

Within a neoplastic milieu, cancer and immune cells can closely interactto generate an immunosuppressive environment by releasingimmunomodulatory factors, which support neoplastic growth. Theexpression of CD39 is increased in many solid tumors (for example,colorectal cancer, head and neck cancer, pancreatic cancer (Kunzli etal., Am J Physiol, 2006, 292: 223-230), bladder cancer, brain cancer,breast cancer, gastric cancer, hepatocellular carcinoma, lung cancer,non-small cell lung cancer (Li et al., Oncoimmunology, 2017, 6: 6),chronic lymphocytic leukemia (Pulte et al., Clin Lymphoma Myeloma Leuk,2011, 11(4): 367-372) and lymphoma, melanoma (Dzhandzhugazyan et al.,FEBS Letters, 1998, 430: 227-230), ovarian cancer, and prostate cancer,among others) suggesting this enzyme is involved in the development andprogression of malignancies. Modulators of CD39 may provide potentialtherapies for these types of cancers.

Interactions between tumor cells and their microenvironment areimportant for tumorigenesis. CD39 can participate in tumor immunoescapeby inhibiting the activation, clonal expansion, and homing oftumor-specific T cells, impairing tumor cell killing by effector Tlymphocytes. In addition to these immunoregulatory roles, CD39 cancontribute directly to the modulation of cancer cell growth,differentiation, invasion, migration, metastasis, and angiogenesis. CD39is important for both the initiation of angiogenesis and the progressionof neovascularization. CD39 on vasculature mediates the angiogenicprocess in mouse models of melanoma, lung, and liver malignancy.

Modulators of CD39 activity may also provide potential therapeutics forthe treatment of CD39 conditions including, but not limited to,autoimmune diseases and infections. In particular, modulators of CD39activity may provide potential therapeutics for diseases such as, forexample, without limitation, Celiac disease (Cook et al., AmericanAcademy of Allergy, Asthma &Immunology, 2017, Article in Press), colitis(Longhi et al., JCI Insight. 2017, 2(9)), thrombotic disease (Marcus etal., Journal of Pharmacology and Experimental Therapeutics, 2003, 305,1: 9-16), HIV infection (zur Wiesch et al., Journal of Virology, 2011,February: 1287-1297), HBV infection, HCV infection, and inflammatorybowel disease (Friedman et al. PNAS, 2009, 106, 39: 16788-16793) andCrohn's disease (Bai et al., J Immunol, 2014, 3366-3377).

SUMMARY

Provided herein are antibodies that selectively bind CD39. In someembodiments, the antibodies bind human CD39. In some embodiments, theantibodies also bind homologs of human CD39.

In some embodiments, the antibodies comprise at least one CDR sequencedefined by a consensus sequence provided in this disclosure. In someembodiments, the antibodies comprise an illustrative CDR, V_(H), orV_(L) sequence provided in this disclosure, heavy chain or light chainprovided in the disclosure, or a variant thereof. In some aspects, thevariant is a variant with one or more conservative amino acidsubstitutions.

Also provided are compositions and kits comprising the antibodies. Insome embodiments, the compositions are pharmaceutical compositions. Anysuitable pharmaceutical composition may be used. In some embodiments,the pharmaceutical composition is a composition for parenteraladministration.

This disclosure also provides methods of using the anti-CD39 antibodiesprovided herein. In some embodiments, the method is a method oftreatment. In some embodiments, the method is a diagnostic method. Insome embodiments, the method is an analytical method. In someembodiments, the method is a method of purifying and/or quantifyingCD39.

In some embodiments, the antibodies are used to treat a disease orcondition. In some aspects, the disease or condition is selected from acancer, autoimmune disease, and infection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a table showing monovalent affinity of anti-huCD39antibodies to recombinant human CD39 extracellular domain. The tableprovides binding kinetics of anti-CD39 antibodies interacting withsoluble recombinant human CD39 (ENTDP1) extracellular domain (ECD) bybiolayer interferometry (ForteBio Octet). Anti-CD39 antibodies werecaptured on an anti-human Fc sensor and exposed to recombinant humanCD39 ECD at concentration ranging from 10-300 nanomolar. The kineticdata was globally fit with a simple 1:1 Langmuir binding model to yieldon-rate (kon) and off-rate (koff) values. The equilibrium dissociationconstants (K_(D)) were calculated from the kon and koff values.

FIGS. 2 A-E show inhibition of enzymatic catabolism of ATP and ADP to Piby human CD39 extracellular domain (ECD). Recombinant human CD39 at afinal concentration of either 10 nanomolar (A-D) or 5 nanomolar (E) wasincubated with anti-CD39 IgGs at a final concentration of either 1micromolar (A-D) or 0.25 micromolar (E) in 25 mM Tris, 5 mM CaCl₂, pH7.5 at room temperature for 2 hours. ATP (500 micromolar) was added tothe reaction and incubated at 37° C. for 60 minutes. Residual ATP levelsin the reaction were measured using the CellTiter-Glo assay. Data valuesare the average of two replicates.

FIG. 2 F shows antibodies that bind to CHO cells expressing human orcyno CD39.

FIG. 3 shows evaluation of antibody binding to MEL-28 (A) and 721 (B)cells. Anti-CD39 antibodies (each antibody clone number indicated in thefigure) were titrated from 15 to 0.001 μg/ml. EC₅₀s were calculatedusing GraphPad Prism Software. The figure represents three independentexperiments.

FIG. 4 provides evaluation of antibody driven inhibition of ATPhydrolysis of CD39 on MEL-28 cells in a short term ATP assay. FIG. 4Ashows the results when anti-CD39 antibodies were compared to thenon-specific small molecule inhibitors POM-1 and ARL. Inhibition isdetermined by decreased phosphate release (Pi). Data is representativeof at least 10 independent experiments. Anti-CD39 antibodies (eachantibody clone number is indicated in the figure) were titrated from 15to 0.001 μg/ml. IC50 values were calculated using GraphPad PrismSoftware, as can be seen in FIG. 4B. Three independent experiments wereperformed.

FIG. 5 provides an illustration of quantification when MEL-28 cells aretreated with CD39 enzymatic inhibitors. FIG. 5A shows evaluation of ATPlevels after incubating MEL-28 cells with a dose titration of anti-CD39antibodies that inhibit enzymatic activity. FIG. 5B provides IC50 valuescalculated using GrapPad Prism. At least three independent experimentswere performed.

FIG. 6 shows that antibodies were evaluated for inhibiting CD39enzymatic activity overnight to MEL-28 cells. FIG. 6A shows anti-CD39antibodies (each number represents a unique clone indicated in thefigure) were titrated from 100 nM to 0.000610 nM. FIG. 6B provide IC50values calculated using GraphPad Prism Software. Three independentexperiments are represented.

FIG. 7 shows results of testing of antibodies for binding to CD39 onhuman and cyno primary B cells. In FIG. 7A, anti-CD39 antibodies weretitrated on purified B cells from healthy donor and detected withanti-human IgG-PE secondary antibody. EC50 was calculated using GrapPadPrism software. In FIG. 7B, anti-CD39 antibodies were titrated on cynoPBMCs and detected using a-human IgG PE secondary antibody. B cells weregated using FlowJo software and EC₅₀s were calculated using GraphPadPrism.

FIG. 8 sets forth antibodies that were evaluated for inhibition of CD39activity on primary human B cells. Anti-CD39 antibodies (each uniqueantibody clone number indicated is in the figure) were titrated from 100to 0.00013 nM.

FIG. 9 provides evaluation of inhibition of CD39 activity on primaryhuman (a) and cyno (b) monocytes. Anti-CD39 antibodies (each numberrepresents a unique antibody clone number as indicated in the figure)were titrated from 100 to 0.00013 nM and incubated with monocytes inpresence of ATP. Phosphate release by CD39 processing of ATP wasquantified using Malachite Green assay.

FIG. 10 shows binding of anti-CD39 antibodies on purified humanCD4⁺CD25⁺CD127^(dim) Treg cells by FACS. Anti-CD39 antibodies weretitrated on purified Treg from healthy donor and detected withanti-human IgG secondary antibody. EC₅₀s were calculated using GraphPadPrism software.

FIG. 11 shows results for antibody ability to inhibit primary Treg CD39activity. CD24⁺CD25⁺CD127^(dim) T regulatory cells were incubated withserially diluted anti-CD39 antibodies and tested for ATPase activityafter addition of exogenous ATP. Free phosphate (Pi) was used as areadout of CD39 activity.

FIG. 12 shows treatment with anti-CD39 antibodies increase the percentof IFN gamma producing CD8⁺ T cells that respond to CMV peptides in anantigen recall response assay.

FIG. 13 shows evaluation of antibodies for inhibition of CD39 activityon MEL-28 (FIG. 13A.) and human monocytes (FIG. 13B.) as compared to theanti-CD39 antibodies generated based on Innate/Orega (BY-40v9) andIgenica (9-8B) and variants thereof. Anti-CD39 antibodies were titratedas indicated and incubated in presence of ATP. Phosphate release by CD39processing of ATP was quantified using Malachite Green assay.

FIGS. 14 A-G provides examples of antibodies. FIG. 14A provides examplesof antibodies that bind soluble recombinant CD39 ECD and cellular CD39but do not inhibit ATPase activity and do not compete with cellularinhibitors for binding to ECD inhibitors. FIG. 14B provides examples ofantibodies that have limited ability to inhibit the ATPase activity ofboth soluble recombinant and cellular CD39 and bin separately from othercellular CD39 inhibitors. FIG. 14C provides example of antibodies thatinhibit the ATPase activity of soluble recombinant CD39 ECD but do notinhibit cellular CD39 and bin separately from other CD39 ECD inhibitors.FIG. 14D provides examples of antibodies that inhibit the ATPaseactivity of ECD and cellular CD39 and bin separately from other CD39 ECDand/or cellular inhibitors. FIG. 14E provides examples of inhibitoryantibodies that make distinct contacts with CD39. FIG. 14E has twotables, Table 1 and Table 2. Table 1 provides examples of inhibitoryantibodies that make distinct contacts with CD39. Table 2 providesexamples of inhibitory antibodies that bind critical yet distinctcontacts residues with CD39. FIG. 14F and FIG. 14G provide FACS plottinghighlighting the importance of certain human CD39 residues.

FIG. 15 shows that anti-CD39 antibodies inhibit CD39 by 75-90%.Anti-CD39 antibodies (100 nanomolar), isotype control antibody (100nanomolar), or ARL (200 micromolar) were incubated with MEL-28 cellsendogenously expressing human CD39 for 2 hours. ATP was then added andthe rate of ATP hydrolysis to Pi by CD39 was monitored using the EnzChekkinetic Pi detection assay. The initial enzyme velocity, ν0, wasdetermined from the linear region of Pi vs. time curve over the first 15minutes post-ATP addition. Each value is the mean of 3 replicates.

FIGS. 16A-B shows that the CD39 inhibitor 29872 is not a competitiveinhibitor due to suppression of V_(max) suppression.

FIG. 17 shows that anti-CD39 antibodies can induce internalization ofCD39 on cyno monocytes.

FIG. 18 provides a comparison of the Kabat and Chothia numbering systemsfor CDR-H1. Adapted from Martin A. C. R. (2010). Protein Sequence andStructure Analysis of Antibody Variable Domains. In R. Kontermann & S.Dübel (Eds.), Antibody Engineering vol. 2 (pp. 33-51). Springer-Verlag,Berlin Heidelberg.

FIG. 19 shows an anti-CD39 antibody increases proliferation ofstimulated CD4⁺ and CD8⁺ T cells.

FIG. 20 shows anti-CD39 antibody increases stimulated PBMC secretion ofINF-γ, TNF-α and IL-2.

FIG. 21 shows anti-CD39 antibody increases stimulated PBMC secretion ofINF-γ, TNF-α, IL-2 and IL-1β.

FIG. 22 shows CD39 inhibition leads to accumulation of ATP and blocksgeneration of adenosine.

DETAILED DESCRIPTION 1. Definitions

Unless otherwise defined, all terms of art, notations and otherscientific terminology used herein are intended to have the meaningscommonly understood by those of skill in the art to which this inventionpertains. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not necessarily be construed torepresent a difference over what is generally understood in the art. Thetechniques and procedures described or referenced herein are generallywell understood and commonly employed using conventional methodologiesby those skilled in the art, such as, for example, the widely utilizedmolecular cloning methodologies described in Sambrook et al., MolecularCloning: A Laboratory Manual 2nd ed. (1989) Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. As appropriate, proceduresinvolving the use of commercially available kits and reagents aregenerally carried out in accordance with manufacturer defined protocolsand/or parameters unless otherwise noted.

As used herein, the singular forms “a,” “an,” and “the” include theplural referents unless the context clearly indicates otherwise.

The term “about” indicates and encompasses an indicated value and arange above and below that value. In certain embodiments, the term“about” indicates the designated value ±10%, ±5%, or ±1%. In certainembodiments, the term “about” indicates the designated value ±onestandard deviation of that value.

The term “combinations thereof” includes every possible combination ofelements to which the term refers.

The terms “CD39” and “CD39 antigen” and “Cluster of Differentiation 39”are used interchangeably herein. CD39 is also known as also known asectonucleoside triphosphate diphosphohydrolase-1 (gene: ENTPD1; protein:NTPDase1, See www.ncbi.nlm.nih.gov/gene/953). CD39 has also beenreferred to as ATPDase and SPG64. Each of the terms set forth may beused interchangeably. Unless specified otherwise, the terms include anyvariants, isoforms and species homologs of human CD39 that are naturallyexpressed by cells, or that are expressed by cells transfected with aCD39 gene. In some embodiments, CD39 proteins include murine CD39. Insome embodiments, CD39 proteins include cynomolgus CD39.

The term “immunoglobulin” refers to a class of structurally relatedproteins generally comprising two pairs of polypeptide chains: one pairof light (L) chains and one pair of heavy (H) chains. In an “intactimmunoglobulin,” all four of these chains are interconnected bydisulfide bonds. The structure of immunoglobulins has been wellcharacterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5(2013) Lippincott Williams & Wilkins, Philadelphia, Pa. Briefly, eachheavy chain typically comprises a heavy chain variable region (V_(H))and a heavy chain constant region (C_(H)). The heavy chain constantregion typically comprises three domains, C_(H1), C_(H2), and C_(H3).Each light chain typically comprises a light chain variable region(V_(L)) and a light chain constant region. The light chain constantregion typically comprises one domain, abbreviated CL.

The term “antibody” describes a type of immunoglobulin molecule and isused herein in its broadest sense. An antibody specifically includesintact antibodies (e.g., intact immunoglobulins), and antibodyfragments. Antibodies comprise at least one antigen-binding domain. Oneexample of an antigen-binding domain is an antigen binding domain formedby a V_(H)-V_(L) dimer. A “CD39 antibody,” “anti-CD39 antibody,” “CD39Ab,” “CD39-specific antibody” or “anti-CD39 Ab” is an antibody, asdescribed herein, which binds specifically to the antigen CD39. In someembodiments, the antibody binds the extracellular domain of CD39.

The V_(H) and V_(L) regions may be further subdivided into regions ofhypervariability (“hypervariable regions (HVRs);” also called“complementarity determining regions” (CDRs)) interspersed with regionsthat are more conserved. The more conserved regions are called frameworkregions (FRs). Each V_(H) and V_(L) generally comprises three CDRs andfour FRs, arranged in the following order (from N-terminus toC-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs are involved inantigen binding, and confer antigen specificity and binding affinity tothe antibody. See Kabat et al., Sequences of Proteins of ImmunologicalInterest 5th ed. (1991) Public Health Service, National Institutes ofHealth, Bethesda, Md., incorporated by reference in its entirety.

The light chain from any vertebrate species can be assigned to one oftwo types, called kappa and lambda, based on the sequence of theconstant domain.

The heavy chain from any vertebrate species can be assigned to one offive different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. Theseclasses are also designated α, δ, ε, γ, and μ, respectively. The IgG andIgA classes are further divided into subclasses on the basis ofdifferences in sequence and function. Humans express the followingsubclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

The amino acid sequence boundaries of a CDR can be determined by one ofskill in the art using any of a number of known numbering schemes,including those described by Kabat et al., supra (“Kabat” numberingscheme); Al-Lazikani et al., 1997, J Mol. Biol., 273:927-948 (“Chothia”numbering scheme); MacCallum et al., 1996, J Mol. Biol. 262:732-745(“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003,27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol.Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which isincorporated by reference in its entirety.

Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1,CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. ForCDR-H1, residue numbering is provided using both the Kabat and Chothianumbering schemes. FIG. 1 provides a comparison of the Kabat and Chothianumbering schemes for CDR-H1. See Martin (2010), supra.

Unless otherwise specified, the numbering scheme used for identificationof a particular CDR herein is the Kabat/Chothia numbering scheme. Wherethe residues encompassed by these two numbering schemes diverge, thenumbering scheme is specified as either Kabat or Chothia.

TABLE 1 Residues in CDRs according to Kabat and Chothia numberingschemes. CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3L89-L97 L89-L97 H1 (Kabat H31-H35B H26-H32 or Numbering) H34* H1(Chothia H31-H35 H26-H32 Numbering) H2 H50-H65 H52-H56 H3 H95-H102H95-H102 *The C-terminus of CDR-H1, when numbered using the Kabatnumbering convention, varies between H32 and H34, depending on thelength of the CDR, as illustrated in FIG. 1.

The “EU numbering scheme” is generally used when referring to a residuein an antibody heavy chain constant region (e.g., as reported in Kabatet al., supra). Unless stated otherwise, the EU numbering scheme is usedto refer to residues in antibody heavy chain constant regions describedherein.

An “antibody fragment” comprises a portion of an intact antibody, suchas the antigen binding or variable region of an intact antibody.Antibody fragments include, for example, Fv fragments, Fab fragments,F(ab′)2 fragments, Fab′ fragments, scFv (sFv) fragments, and scFv-Fcfragments.

“Fv” fragments comprise a non-covalently-linked dimer of one heavy chainvariable domain and one light chain variable domain.

“Fab” fragments comprise, in addition to the heavy and light chainvariable domains, the constant domain of the light chain and the firstconstant domain (C_(H1)) of the heavy chain. Fab fragments may begenerated, for example, by papain digestion of a full-length antibody.

“F(ab′)₂” fragments contain two Fab′ fragments joined, near the hingeregion, by disulfide bonds. F(ab′)₂ fragments may be generated, forexample, by pepsin digestion of an intact antibody. The F(ab′) fragmentscan be dissociated, for example, by treatment with β-mercaptoethanol.

“Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a V_(H)domain and a V_(L) domain in a single polypeptide chain. The V_(H) andV_(L) are generally linked by a peptide linker. See Plückthun A. (1994).Antibodies from Escherichia coli. In Rosenberg M. & Moore G. P. (Eds.),The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315).Springer-Verlag, New York, incorporated by reference in its entirety.“scFv-Fc” fragments comprise an scFv attached to an Fc domain. Forexample, an Fc domain may be attached to the C-terminal of the scFv. TheFc domain may follow the V_(H) or V_(L), depending on the orientation ofthe variable domains in the scFv (i.e., V_(H)-V_(L) or V_(L)-V_(H)). Anysuitable Fc domain known in the art or described herein may be used.

The term “monoclonal antibody” refers to an antibody from a populationof substantially homogeneous antibodies. A population of substantiallyhomogeneous antibodies comprises antibodies that are substantiallysimilar and that bind the same epitope(s), except for variants that maynormally arise during production of the monoclonal antibody. Suchvariants are generally present in only minor amounts. A monoclonalantibody is typically obtained by a process that includes the selectionof a single antibody from a plurality of antibodies. For example, theselection process can be the selection of a unique clone from aplurality of clones, such as a pool of hybridoma clones, phage clones,yeast clones, bacterial clones, or other recombinant DNA clones. Theselected antibody can be further altered, for example, to improveaffinity for the target (“affinity maturation”), to humanize theantibody, to improve its production in cell culture, and/or to reduceits immunogenicity in a subject.

The term “chimeric antibody” refers to an antibody in which a portion ofthe heavy and/or light chain is derived from a particular source orspecies, while the remainder of the heavy and/or light chain is derivedfrom a different source or species.

“Humanized” forms of non-human antibodies are chimeric antibodies thatcontain minimal sequence derived from the non-human antibody. Ahumanized antibody is generally a human immunoglobulin (recipientantibody) in which residues from one or more CDRs are replaced byresidues from one or more CDRs of a non-human antibody (donor antibody).The donor antibody can be any suitable non-human antibody, such as amouse, rat, rabbit, chicken, or non-human primate antibody having adesired specificity, affinity, or biological effect. In some instances,selected framework region residues of the recipient antibody arereplaced by the corresponding framework region residues from the donorantibody. Humanized antibodies may also comprise residues that are notfound in either the recipient antibody or the donor antibody. Suchmodifications may be made to further refine antibody function. Forfurther details, see Jones et al., Nature, 1986, 321:522-525; Riechmannet al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol.,1992, 2:593-596, each of which is incorporated by reference in itsentirety.

A “human antibody” is one which possesses an amino acid sequencecorresponding to that of an antibody produced by a human or a humancell, or derived from a non-human source that utilizes a human antibodyrepertoire or human antibody-encoding sequences (e.g., obtained fromhuman sources or designed de novo). Human antibodies specificallyexclude humanized antibodies.

An “isolated antibody” is one that has been separated and/or recoveredfrom a component of its natural environment. Components of the naturalenvironment may include enzymes, hormones, and other proteinaceous ornonproteinaceous materials. In some embodiments, an isolated antibody ispurified to a degree sufficient to obtain at least 15 residues ofN-terminal or internal amino acid sequence, for example by use of aspinning cup sequenator. In some embodiments, an isolated antibody ispurified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) underreducing or nonreducing conditions, with detection by Coomassie blue orsilver stain. An isolated antibody includes an antibody in situ withinrecombinant cells, since at least one component of the antibody'snatural environment is not present. In some aspects, an isolatedantibody is prepared by at least one purification step.

In some embodiments, an isolated antibody is purified to at least 80%,85%, 90%, 95%, or 99% by weight. In some embodiments, an isolatedantibody is provided as a solution comprising at least 85%, 90%, 95%,98%, 99% to 100% by weight of an antibody, the remainder of the weightcomprising the weight of other solutes dissolved in the solvent.

“Affinity” refers to the strength of the sum total of non-covalentinteractions between a single binding site of a molecule (e.g., anantibody) and its binding partner (e.g., an antigen). Unless indicatedotherwise, as used herein, “binding affinity” refers to intrinsicbinding affinity, which reflects a 1:1 interaction between members of abinding pair (e.g., antibody and antigen). The affinity of a molecule Xfor its partner Y can generally be represented by the dissociationconstant (K_(D)). Affinity can be measured by common methods known inthe art, including those described herein. Affinity can be determined,for example, using surface plasmon resonance (SPR) technology, such as aBiacore® instrument.

With regard to the binding of an antibody to a target molecule, theterms “specific binding,” “specifically binds to,” “specific for,”“selectively binds,” and “selective for” a particular antigen (e.g., apolypeptide target) or an epitope on a particular antigen mean bindingthat is measurably different from a non-specific or non-selectiveinteraction. Specific binding can be measured, for example, bydetermining binding of a molecule compared to binding of a controlmolecule. Specific binding can also be determined by competition with acontrol molecule that is similar to the target, such as an excess ofnon-labeled target. In that case, specific binding is indicated if thebinding of the labeled target to a probe is competitively inhibited bythe excess non-labeled target.

The term “k_(d)” (sec⁻¹), as used herein, refers to the dissociationrate constant of a particular antibody-antigen interaction. This valueis also referred to as the koff value.

The term “k_(a)” (M⁻¹×sec⁻¹), as used herein, refers to the associationrate constant of a particular antibody-antigen interaction. This valueis also referred to as the k_(on) value.

The term “K_(D)” (M), as used herein, refers to the dissociationequilibrium constant of a particular antibody-antigen interaction.K_(D)=k_(d)/k_(a).

The term “K_(A)” (M⁻¹), as used herein, refers to the associationequilibrium constant of a particular antibody-antigen interaction.K_(A)=k_(a)/k_(d).

An “affinity matured” antibody is one with one or more alterations inone or more CDRs or FRs that result in an improvement in the affinity ofthe antibody for its antigen, compared to a parent antibody which doesnot possess the alteration(s). In one embodiment, an affinity maturedantibody has nanomolar or picomolar affinity for the target antigen.Affinity matured antibodies may be produced using a variety of methodsknown in the art. For example, Marks et al. (Bio/Technology, 1992,10:779-783, incorporated by reference in its entirety) describesaffinity maturation by V_(H) and V_(L) domain shuffling. Randommutagenesis of CDR and/or framework residues is described by, forexample, Barbas et al. (Proc. Nat. Acad. Sci. USA., 1994, 91:3809-3813);Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol.,1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199;and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which isincorporated by reference in its entirety.

When used herein in the context of two or more antibodies, the term“competes with” or “cross-competes with” indicates that the two or moreantibodies compete for binding to an antigen (e.g., CD39). In oneexemplary assay, CD39 is coated on a plate and allowed to bind a firstantibody, after which a second, labeled antibody is added. If thepresence of the first antibody reduces binding of the second antibody,then the antibodies compete. The term “competes with” also includescombinations of antibodies where one antibody reduces binding of anotherantibody, but where no competition is observed when the antibodies areadded in the reverse order. However, in some embodiments, the first andsecond antibodies inhibit binding of each other, regardless of the orderin which they are added. In some embodiments, one antibody reducesbinding of another antibody to its antigen by at least 50%, at least60%, at least 70%, at least 80%, or at least 90%.

The term “epitope” means a portion of an antigen capable of specificbinding to an antibody. Epitopes frequently consist ofsurface-accessible amino acid residues and/or sugar side chains and mayhave specific three dimensional structural characteristics, as well asspecific charge characteristics. Conformational and non-conformationalepitopes are distinguished in that the binding to the former but not thelatter is lost in the presence of denaturing solvents. An epitope maycomprise amino acid residues that are directly involved in the binding,and other amino acid residues, which are not directly involved in thebinding. The epitope to which an antibody binds can be determined usingknown techniques for epitope determination such as, for example, testingfor antibody binding to CD39 variants with different point-mutations.

Percent “identity” between a polypeptide sequence and a referencesequence is defined as the percentage of amino acid residues in thepolypeptide sequence that are identical to the amino acid residues inthe reference sequence, after aligning the sequences and introducinggaps, if necessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent amino acid sequenceidentity can be achieved in various ways that are within the skill inthe art, for instance, using publicly available computer software suchas BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGAsoftware. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.

A “conservative substitution” or a “conservative amino acidsubstitution,” refers to the substitution of one or more amino acidswith one or more chemically or functionally similar amino acids.Conservative substitution tables providing similar amino acids are wellknown in the art. Polypeptide sequences having such substitutions areknown as “conservatively modified variants.” Such conservativelymodified variants are in addition to and do not exclude polymorphicvariants, interspecies homologs, and alleles. By way of example, thefollowing groups of amino acids are considered conservativesubstitutions for one another.

Acidic Residues D and E Basic Residues K, R, and H Hydrophilic UnchargedResidues S, T, N, and Q Aliphatic Uncharged Residues G, A, V, L, and INon-polar Uncharged Residues C, M, and P Aromatic Residues F, Y, and WAlcohol Group-Containing Residues S and T Aliphatic Residues I, L, V,and M Cycloalkenyl-associated Residues F, H, W, and Y HydrophobicResidues A, C, F, G, H, I, L, M, R, T, V, W, and Y Negatively ChargedResidues D and E Polar Residues C, D, E, H, K, N, Q, R, S, and TPositively Charged Residues H, K, and R Small Residues A, C, D, G, N, P,S, T, and V Very Small Residues A, G, and S Residues Involved in Turn A,C, D, E, G, H, K, Formation N, Q, R, S, P, and T Flexible Residues Q, T,K, S, G, P, D, E, and R Group 1 A, S, and T Group 2 D and E Group 3 Nand Q Group 4 R and K Group 5 I, L, and M Group 6 F, Y, and W Group A Aand G Group B D and E Group C N and Q Group D R, K, and H Group E I, L,M, V Group F F, Y, and W Group G S and T Group H C and MAdditional conservative substitutions may be found, for example, inCreighton, Proteins: Structures and Molecular Properties 2nd ed. (1993)W. H. Freeman & Co., New York, N.Y. An antibody generated by making oneor more conservative substitutions of amino acid residues in a parentantibody is referred to as a “conservatively modified variant.”

The term “amino acid” refers to the twenty common naturally occurringamino acids. Naturally occurring amino acids include alanine (Ala; A),arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine(Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G);histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys;K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P),serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr;Y), and valine (Val; V).

“Treating” or “treatment” of any disease or disorder refers, in certainembodiments, to ameliorating a disease or disorder that exists in asubject. In another embodiment, “treating” or “treatment” includesameliorating at least one physical parameter, which may be indiscernibleby the subject. In yet another embodiment, “treating” or “treatment”includes modulating the disease or disorder, either physically (e.g.,stabilization of a discernible symptom) or physiologically (e.g.,stabilization of a physical parameter) or both. In yet anotherembodiment, “treating” or “treatment” includes delaying or preventingthe onset of the disease or disorder.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount of an antibody or compositionthat when administered to a subject is effective to treat a disease ordisorder.

As used herein, the term “subject” means a mammalian subject. Exemplarysubjects include, but are not limited to humans, monkeys, dogs, cats,mice, rats, cows, horses, camels, avians, goats, and sheep. In certainembodiments, the subject is a human. In some embodiments, the subjecthas cancer, an autoimmune disease or condition, and/or an infection thatcan be treated with an antibody provided herein. In some embodiments,the subject is a human that is suspected to have cancer, an autoimmunedisease or condition, and/or an infection.

2. Antibodies

Provided herein are antibodies that selectively bind human CD39, as wellas the nucleic acids that encode the antibodies. In some aspects, theantibody selectively binds to the extracellular domain of human CD39.

In some embodiments, the antibody binds to homologs of human CD39. Insome aspects, the antibody binds to a homolog of human CD39 from aspecies selected from monkeys, mice, dogs, cats, rats, cows, horses,goats, and sheep. In some aspects, the homolog is a cynomolgus monkeyhomolog. In some aspects, the homolog is a murine homolog.

In some embodiments, the antibody has one or more CDRs having particularlengths, in terms of the number of amino acid residues. In someembodiments, the Chothia CDR-H1 of the antibody is 6, 7, 8, or 9residues in length. In some embodiments, the Kabat CDR-H1 of theantibody is 4, 5, 6, or 7 residues in length. In some embodiments, theChothia CDR-H2 of the antibody is 5, 6, or 7 residues in length. In someembodiments, the Kabat CDR-H2 of the antibody is 15, 16, 17, or 18residues in length. In some embodiments, the Kabat/Chothia CDR-H3 of theantibody is 5, 6, 7, 8, 9, 10, 11, or 12 residues in length.

In some aspects, the Kabat/Chothia CDR-L1 of the antibody is 9, 10, 11,12, 13, 14, 15, or 16 residues in length. In some aspects, theKabat/Chothia CDR-L2 of the antibody is 6, 7, or 8 residues in length.In some aspects, the Kabat/Chothia CDR-L3 of the antibody is 8, 9, 10,11, or 12 residues in length.

In some embodiments, the antibody comprises a light chain. In someaspects, the light chain is a kappa light chain. In some aspects, thelight chain is a lambda light chain.

In some embodiments, the antibody comprises a heavy chain. In someaspects, the heavy chain is an IgA. In some aspects, the heavy chain isan IgD. In some aspects, the heavy chain is an IgE. In some aspects, theheavy chain is an IgG. In some aspects, the heavy chain is an IgM. Insome aspects, the heavy chain is an IgG1. In some aspects, the heavychain is an IgG2. In some aspects, the heavy chain is an IgG3. In someaspects, the heavy chain is an IgG4. In some aspects, the heavy chain isan IgA1. In some aspects, the heavy chain is an IgA2.

In some embodiments, the antibody is an antibody fragment. In someaspects, the antibody fragment is an Fv fragment. In some aspects, theantibody fragment is a Fab fragment. In some aspects, the antibodyfragment is a F(ab′)₂ fragment. In some aspects, the antibody fragmentis a Fab′ fragment. In some aspects, the antibody fragment is an scFv(sFv) fragment. In some aspects, the antibody fragment is an scFv-Fcfragment.

In some embodiments, the antibody is a monoclonal antibody. In someembodiments, the antibody is a polyclonal antibody.

In some embodiments, the antibody is a chimeric antibody. In someembodiments, the antibody is a humanized antibody. In some embodiments,the antibody is a human antibody.

In some embodiments, the antibody is an affinity matured antibody. Insome aspects, the antibody is an affinity matured antibody derived froman illustrative sequence provided in this disclosure.

In some aspects, the antibody inhibits conversion by CD39 of ATP to ADPand/or ADP to AMP. In some aspects, the antibody decreases the levels ofphosphate, ADP, AMP, and/or adenosine and/or increases the levels ofATP.

In some embodiments, the antibody increases proliferation of stimulatedCD4⁺ and CD8⁺ T cells. In some embodiments, the antibody increasesstimulated PBMC secretion of INF-γ, TNF-α, IL-2, and/or IL-1β.

In some embodiments, the antibody increases a T effector cell function.In some embodiments, the antibody decreases the number of regulatory Tcells in tissues or in circulation. In some embodiments, the antibodysuppresses a regulatory or T cell activity. In some embodiments, theantibody increase B cell function. In some embodiments, the antibodyincreases antigen presenting cell function. In some embodiments, theantibody decreases or prevents activation of phospho antigen specific Tcells selected from MAIT cells and gamma delta T cells.

In some aspects, the decrease is about or less than a 10% decrease,about or less than a 20% decrease, about or less than a 30% decrease,about or less than a 40% decrease, about or less than a 50% decrease,about or less than a 60% decrease, about or less than a 70% decrease,about or less than an 80% decrease, about or less than a 90% decrease,or about a complete decrease. In some aspects, the increase is about orgreater than a 10% increase, about or greater than a 20% increase, aboutor greater than a 30% increase, about or greater than a 40% increase,about or greater than a 50% increase, about or greater than a 60%increase, about or greater than a 70% increase, about or greater than an80% increase, about or greater than a 90% increase, or a completeincrease.

Given that CD39 degrades ATP and ADP to adenosine, CD39 can be viewed asan immunological switch that shifts ATP-driven pro-inflammatory immunecell activity toward an anti-inflammatory state mediated by adenosine.CD39 has a role in regulating the function of several immune cell types,including lymphocytes, neutrophils, monocytes/macrophages, dendriticcells, and endothelial cells and shifting the switch can have asignificant impact on disease. For example, the generation of adenosinevia CD39 is recognized as a major mechanism of regulatory T cell (Treg)immunosuppressive function.

The antibodies provided herein may be useful for the treatment of avariety of diseases and conditions, including cancers, autoimmunediseases, and infections. In some embodiments, the antibody inhibitsCD39 function on tumor cells. In some embodiments, the antibody inhibitsangiogenesis.

The frequency of CD39⁺ Tregs and the expression on the cell surface isincreased in some human cancers, and the importance of CD39⁺ Tregs inpromoting tumor growth and metastasis has been demonstrated usingseveral in vivo models. Immunohistochemical staining of normal and tumortissues has revealed that CD39 expression is significantly higher inseveral types of human cancer than in normal tissues. In cancerspecimens, CD39 is expressed by infiltrating lymphocytes, the tumorstroma, and/or tumor cells. CD39 in cancer cells displays ATPaseactivity and generates adenosine. CD39⁺ cancer cells inhibited theproliferation of CD4 and CD8 T cells and the generation of cytotoxiceffector CD8 T cells (CTL) in a CD39− and adenosine-dependent manner.

2.1. CDR-H3 Sequences

In some embodiments, the antibody comprises a CDR-H3 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 82-109. In some aspects, the antibodycomprises a CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 82. In some aspects, the antibody comprises aCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 83. In some aspects, the antibody comprises a CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 84.In some aspects, the antibody comprises a CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 85. In someaspects, the antibody comprises a CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 86. In some aspects, theantibody comprises a CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 87. In some aspects, the antibodycomprises a CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 88. In some aspects, the antibody comprises aCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 89. In some aspects, the antibody comprises a CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 90.In some aspects, the antibody comprises a CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 91. In someaspects, the antibody comprises a CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 92. In some aspects, theantibody comprises a CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 93. In some aspects, the antibodycomprises a CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 94. In some aspects, the antibody comprises aCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 95. In some aspects, the antibody comprises a CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 96.In some aspects, the antibody comprises a CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 97. In someaspects, the antibody comprises a CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 98. In some aspects, theantibody comprises a CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 99. In some aspects, the antibodycomprises a CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 100. In some aspects, the antibody comprises aCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 101. In some aspects, the antibody comprises a CDR-H3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 102. In some aspects, the antibody comprises a CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 103.In some aspects, the antibody comprises a CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 104. In someaspects, the antibody comprises a CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 105. In some aspects, theantibody comprises a CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 106. In some aspects, the antibodycomprises a CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 107. In some aspects, the antibody comprises aCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 108. In some aspects, the antibody comprises a CDR-H3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 109.

In some aspects, the CDR-H3 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-H3 sequence provided inthis disclosure. In some aspects, the CDR-H3 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3sequences provided in this disclosure. In some aspects, the CDR-H3sequence comprises, consists of, or consists essentially of any of theillustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

2.2. V_(H) Sequences Comprising Illustrative CDRs

In some embodiments, the antibody comprises a V_(H) sequence comprisingone or more CDR-H sequences comprising, consisting of, or consistingessentially of one or more illustrative CDR-H sequences provided in thisdisclosure, and variants thereof.

2.2.1. V_(H) Sequences Comprising Illustrative Kabat CDRs

In some embodiments, the antibody comprises a V_(H) sequence comprisingone or more Kabat CDR-H sequences comprising, consisting of, orconsisting essentially of one or more illustrative Kabat CDR-H sequencesprovided in this disclosure, and variants thereof.

2.2.1.1. Kabat CDR-H3

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 82. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 83. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 84.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 85. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 86. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 87.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 88. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 89. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 90.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 91. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 92. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 93.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 94. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 95. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 96.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 97. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 98. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 99.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 100. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 101. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 102.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 103. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 104. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 105.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 106. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 107. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 108.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 109.

2.2.1.2. Kabat CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H2 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 63-81. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 63. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 64. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 65.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 66. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H2 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 67. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 68.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 69. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H2 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 70. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 71.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 72. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H2 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 73. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 74.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 75. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H2 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 76. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 77.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 78. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H2 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 79. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 80.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 81.

2.2.1.3. Kabat CDR-H1

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 25-45. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 25. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 26. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 27.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 28. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 29. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 30.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 31. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 32. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 33.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 34. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 35. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 36.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 37. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 38. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 39.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 40. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 41. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 42.In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 43. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 44. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 45.

2.2.1.4. Kabat CDR-H3+Kabat CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109, and a KabatCDR-H2 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 63-81. In some aspects, the KabatCDR-H3 sequence and the Kabat CDR-H2 sequence are both from a singleillustrative V_(H) sequence provided in this disclosure. For example, insome aspects, the Kabat CDR-H3 and Kabat CDR-H2 are both from a singleillustrative V_(H) sequence selected from SEQ ID NOs: 179-218.

2.2.1.5. Kabat CDR-H3+Kabat CDR-H1

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109, and a KabatCDR-H1 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 25-45. In some aspects, the KabatCDR-H3 sequence and the Kabat CDR-H1 sequence are both from a singleillustrative V_(H) sequence provided in this disclosure. For example, insome aspects, the Kabat CDR-H3 and Kabat CDR-H1 are both from a singleillustrative V_(H) sequence selected from SEQ ID NOs: 179-218.

2.2.1.6. Kabat CDR-H1+Kabat CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 25-45 and a KabatCDR-H2 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 63-81. In some aspects, the KabatCDR-H1 sequence and the Kabat CDR-H2 sequence are both from a singleillustrative V_(H) sequence provided in this disclosure. For example, insome aspects, the Kabat CDR-H1 and Kabat CDR-H2 are both from a singleillustrative V_(H) sequence selected from SEQ ID NOs: 179-218.

2.2.1.7. Kabat CDR-H1+Kabat CDR-H2+Kabat CDR-H3

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 25-45, a KabatCDR-H2 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 63-81, and a Kabat CDR-H3 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 82-109. In some aspects, the Kabat CDR-H1sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all froma single illustrative V_(H) sequence provided in this disclosure. Forexample, in some aspects, the Kabat CDR-H1, Kabat CDR-H2, and KabatCDR-H3 are all from a single illustrative V_(H) sequence selected fromSEQ ID NOs: 179-218.

In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 63, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 82. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a KabatCDR-H2 sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 83. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3sequence comprising SEQ ID NO: 84. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 64, and aKabat CDR-H3 sequence comprising SEQ ID NO: 85. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO:64, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 86. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 66, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 82. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a KabatCDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 82. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3sequence comprising SEQ ID NO: 82. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 28, a Kabat CDR-H2 sequence comprising SEQ ID NO: 67, and aKabat CDR-H3 sequence comprising SEQ ID NO: 82. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 29, a Kabat CDR-H2 sequence comprising SEQ ID NO:68, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 82. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 64, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 82. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a KabatCDR-H2 sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:31, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3sequence comprising SEQ ID NO: 88. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 32, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and aKabat CDR-H3 sequence comprising SEQ ID NO: 89. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 33, a Kabat CDR-H2 sequence comprising SEQ ID NO:70, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 90. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 34, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 72, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 91. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a KabatCDR-H2 sequence comprising SEQ ID NO: 71, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 92. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:35, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3sequence comprising SEQ ID NO: 93. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 33, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and aKabat CDR-H3 sequence comprising SEQ ID NO: 92. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 36, a Kabat CDR-H2 sequence comprising SEQ ID NO:72, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 87. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 30, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 73, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 87. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 37, a KabatCDR-H2 sequence comprising SEQ ID NO: 74, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:38, a Kabat CDR-H2 sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3sequence comprising SEQ ID NO: 94. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 39, a Kabat CDR-H2 sequence comprising SEQ ID NO: 76, and aKabat CDR-H3 sequence comprising SEQ ID NO: 95. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 40, a Kabat CDR-H2 sequence comprising SEQ ID NO:76, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 96. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 39, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 76, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 94. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a KabatCDR-H2 sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 97. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:41, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3sequence comprising SEQ ID NO: 98. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 41, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 99. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 41, a Kabat CDR-H2 sequence comprising SEQ ID NO:69, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 100. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 75, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 101. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 42, a KabatCDR-H2 sequence comprising SEQ ID NO: 78, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 102. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:38, a Kabat CDR-H2 sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3sequence comprising SEQ ID NO: 103. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 43, a Kabat CDR-H2 sequence comprising SEQ ID NO: 79, and aKabat CDR-H3 sequence comprising SEQ ID NO: 104. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 38, a Kabat CDR-H2 sequence comprising SEQ ID NO:69, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 103. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 69, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 106. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a KabatCDR-H2 sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 107. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:44, a Kabat CDR-H2 sequence comprising SEQ ID NO: 80, and a Kabat CDR-H3sequence comprising SEQ ID NO: 108. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 45, a Kabat CDR-H2 sequence comprising SEQ ID NO: 81, and aKabat CDR-H3 sequence comprising SEQ ID NO: 109.

In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 65, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 83. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a KabatCDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 84. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3sequence comprising SEQ ID NO: 85. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and aKabat CDR-H3 sequence comprising SEQ ID NO: 86. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO:64, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 84. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 64, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 86. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 27, a KabatCDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 83. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3sequence comprising SEQ ID NO: 86. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 30, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and aKabat CDR-H3 sequence comprising SEQ ID NO: 93. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 30, a Kabat CDR-H2 sequence comprising SEQ ID NO:73, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 87. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 30, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 72, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 87. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a KabatCDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:31, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3sequence comprising SEQ ID NO: 87. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 31, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and aKabat CDR-H3 sequence comprising SEQ ID NO: 87. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 32, a Kabat CDR-H2 sequence comprising SEQ ID NO:71, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 87. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 33, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 71, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 87. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 33, a KabatCDR-H2 sequence comprising SEQ ID NO: 72, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:33, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3sequence comprising SEQ ID NO: 87. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 33, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and aKabat CDR-H3 sequence comprising SEQ ID NO: 93. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 33, a Kabat CDR-H2 sequence comprising SEQ ID NO:70, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 93. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 34, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 72, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 87. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a KabatCDR-H2 sequence comprising SEQ ID NO: 71, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87. In some aspects, the antibody comprises aV_(H) sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO:35, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3sequence comprising SEQ ID NO: 87. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 35, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and aKabat CDR-H3 sequence comprising SEQ ID NO: 90. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 30, a Kabat CDR-H2 sequence comprising SEQ ID NO:70, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 87. In someaspects, the antibody comprises a V_(H) sequence comprising a KabatCDR-H1 sequence comprising SEQ ID NO: 39, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 76, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 94.

2.2.1.8. Variants of V_(H) Sequences Comprising Illustrative Kabat CDRs

In some embodiments, the V_(H) sequences provided herein comprise avariant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequenceprovided in this disclosure.

In some aspects, the Kabat CDR-H3 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Kabat CDR-H3sequence provided in this disclosure. In some aspects, the Kabat CDR-H3sequence comprises, consists of, or consists essentially of a sequencehaving at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of theillustrative Kabat CDR-H3 sequences provided in this disclosure. In someaspects, the Kabat CDR-H3 sequence comprises, consists of, or consistsessentially of any of the illustrative Kabat CDR-H3 sequences providedin this disclosure, with 1, 2, or 3 amino acid substitutions. In someaspects, the amino acid substitutions are conservative amino acidsubstitutions.

In some aspects, the Kabat CDR-H2 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Kabat CDR-H2sequence provided in this disclosure. In some aspects, the Kabat CDR-H2sequence comprises, consists of, or consists essentially of a sequencehaving at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of theillustrative Kabat CDR-H2 sequences provided in this disclosure. In someaspects, the Kabat CDR-H2 sequence comprises, consists of, or consistsessentially of any of the illustrative Kabat CDR-H2 sequences providedin this disclosure, with 1, 2, or 3 amino acid substitutions. In someaspects, the amino acid substitutions are conservative amino acidsubstitutions.

In some aspects, the Kabat CDR-H1 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Kabat CDR-H1sequence provided in this disclosure. In some aspects, the Kabat CDR-H1sequence comprises, consists of, or consists essentially of a sequencehaving at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of theillustrative Kabat CDR-H1 sequences provided in this disclosure. In someaspects, the Kabat CDR-H1 sequence comprises, consists of, or consistsessentially of any of the illustrative Kabat CDR-H1 sequences providedin this disclosure, with 1, 2, or 3 amino acid substitutions. In someaspects, the amino acid substitutions are conservative amino acidsubstitutions.

2.2.2. V_(H) Sequences Comprising Illustrative Chothia CDRs

In some embodiments, the antibody comprises a V_(H) sequence comprisingone or more Chothia CDR-H sequences comprising, consisting of, orconsisting essentially of one or more illustrative Chothia CDR-Hsequences provided in this disclosure, and variants thereof.

2.2.2.1. Chothia CDR-H3

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 82. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 83. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 84.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 85. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 86. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 87. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 88. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 89.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 90. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 91. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 92. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 93. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 94.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 95. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 96. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 97. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 98. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 99.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 100. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 101. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 102. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 103. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 104.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 105. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 106. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 107. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 108. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 109.

2.2.2.2. Chothia CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H2 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 46-62. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 46. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 47. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 48.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 49. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H2 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 50. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 51. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 52. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 53.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 54. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H2 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 55. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 56. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 57. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 58.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 59. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H2 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 60. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 61. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H2 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 62.

2.2.2.3. Chothia CDR-H1

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 1-24. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 1. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 2. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 3. Insome aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 4. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 5. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 6. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 7. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 8. Insome aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 9. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 10. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 11. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 12. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 13.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 14. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 15. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 16. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 17. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 18.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 19. In some aspects, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 20. In someaspects, the antibody comprises a V_(H) sequence comprising a ChothiaCDR-H1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 21. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 22. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 23.In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 24.

2.2.2.4. Chothia CDR-H3+Chothia CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109, and aChothia CDR-H2 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 46-62. In someaspects, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence areboth from a single illustrative V_(H) sequence provided in thisdisclosure. For example, in some aspects, the Chothia CDR-H3 and ChothiaCDR-H2 are both from a single illustrative V_(H) sequence selected fromSEQ ID NOs: 179-218.

2.2.2.5. Chothia CDR-H3+Chothia CDR-H1

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H3 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 82-109, and aChothia CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 1-24. In someaspects, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence areboth from a single illustrative V_(H) sequence provided in thisdisclosure. For example, in some aspects, the Chothia CDR-H3 and ChothiaCDR-H1 are both from a single illustrative V_(H) sequence selected fromSEQ ID NOs: 179-218.

2.2.2.6. Chothia CDR-H1+Chothia CDR-H2

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 1-24 and a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 46-62. In some aspects, the ChothiaCDR-H1 sequence and the Chothia CDR-H2 sequence are both from a singleillustrative V_(H) sequence provided in this disclosure. For example, insome aspects, the Chothia CDR-H1 and Chothia CDR-H2 are both from asingle illustrative V_(H) sequence selected from SEQ ID NOs: 179-218.

2.2.2.7. Chothia CDR-H1+Chothia CDR-H2+Chothia CDR-H3

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising, consisting of, or consistingessentially of a sequence selected from SEQ ID NOs: 1-24, a ChothiaCDR-H2 sequence comprising, consisting of, or consisting essentially ofa sequence selected from SEQ ID NOs: 46-62, and a Chothia CDR-H3sequence comprising, consisting of, or consisting essentially of asequence selected from SEQ ID NOs: 82-109. In some aspects, the ChothiaCDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequenceare all from a single illustrative V_(H) sequence provided in thisdisclosure. For example, in some aspects, the Chothia CDR-H1, ChothiaCDR-H2, and Chothia CDR-H3 are all from a single illustrative V_(H)sequence selected from SEQ ID NOs: 179-218.

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 83. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 1, a Chothia CDR-H2 sequence comprising SEQ ID NO:46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 84. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 85. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 3, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 86. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 4, a Chothia CDR-H2 sequence comprising SEQ ID NO:46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 5, a Chothia CDR-H2 sequence comprising SEQ ID NO: 49, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 82. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 6, a Chothia CDR-H2 sequence comprising SEQ ID NO:50, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 7, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO:52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 88. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 9, a Chothia CDR-H2sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 89. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and aChothia CDR-H3 sequence comprising SEQ ID NO: 90. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 11, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 54, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 91.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 92. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and aChothia CDR-H3 sequence comprising SEQ ID NO: 93. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 92.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2sequence comprising SEQ ID NO: 54, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 15, a Chothia CDR-H2 sequence comprising SEQ ID NO: 55, and aChothia CDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 56, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a Chothia CDR-H2sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 94. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 57, and aChothia CDR-H3 sequence comprising SEQ ID NO: 95. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 19, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 57, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 96.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a Chothia CDR-H2sequence comprising SEQ ID NO: 57, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 94. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 17, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and aChothia CDR-H3 sequence comprising SEQ ID NO: 97. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 22, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 98.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 22, a Chothia CDR-H2sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 99. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 22, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and aChothia CDR-H3 sequence comprising SEQ ID NO: 100. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 101.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a Chothia CDR-H2sequence comprising SEQ ID NO: 59, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 102. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 17, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and aChothia CDR-H3 sequence comprising SEQ ID NO: 103. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 23, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 60, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 104.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a Chothia CDR-H2sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 105. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 17, a Chothia CDR-H2 sequence comprising SEQ ID NO: 51, and aChothia CDR-H3 sequence comprising SEQ ID NO: 106. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 107.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a Chothia CDR-H2sequence comprising SEQ ID NO: 61, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 108. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 17, a Chothia CDR-H2 sequence comprising SEQ ID NO: 62, and aChothia CDR-H3 sequence comprising SEQ ID NO: 109.

In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 83. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 46, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 84. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 85. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 2, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 86. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO: 47, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 84. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 86. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 83. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 1, a Chothia CDR-H2 sequence comprising SEQ ID NO: 46, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 86. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprising SEQ IDNO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 93. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 10, a Chothia CDR-H2sequence comprising SEQ ID NO: 55, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 54, and aChothia CDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 8, a Chothia CDR-H2sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO: 53, and a ChothiaCDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments, theantibody comprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 9, a Chothia CDR-H2 sequence comprising SEQ ID NO:53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87. In someembodiments, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 10, a Chothia CDR-H2sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 54, and aChothia CDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 10, a Chothia CDR-H2sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 93. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 10, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and aChothia CDR-H3 sequence comprising SEQ ID NO: 93. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 11, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 54, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 52, and aChothia CDR-H3 sequence comprising SEQ ID NO: 87. In some embodiments,the antibody comprises a V_(H) sequence comprising a Chothia CDR-H1sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprisingSEQ ID NO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 90.In some embodiments, the antibody comprises a V_(H) sequence comprisinga Chothia CDR-H1 sequence comprising SEQ ID NO: 15, a Chothia CDR-H2sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87. In some embodiments, the antibody comprises aV_(H) sequence comprising a Chothia CDR-H1 sequence comprising SEQ IDNO: 18, a Chothia CDR-H2 sequence comprising SEQ ID NO: 57, and aChothia CDR-H3 sequence comprising SEQ ID NO: 94.

2.2.2.8. Variants of V_(H) Sequences Comprising Illustrative ChothiaCDRs

In some embodiments, the V_(H) sequences provided herein comprise avariant of an illustrative Chothia CDR-H3, CDR-H2, and/or CDR-H1sequence provided in this disclosure.

In some aspects, the Chothia CDR-H3 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Chothia CDR-H3sequence provided in this disclosure. In some aspects, the ChothiaCDR-H3 sequence comprises, consists of, or consists essentially of asequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity withany of the illustrative Chothia CDR-H3 sequences provided in thisdisclosure. In some aspects, the Chothia CDR-H3 sequence comprises,consists of, or consists essentially of any of the illustrative ChothiaCDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

In some aspects, the Chothia CDR-H2 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Chothia CDR-H2sequence provided in this disclosure. In some aspects, the ChothiaCDR-H2 sequence comprises, consists of, or consists essentially of asequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity withany of the illustrative Chothia CDR-H2 sequences provided in thisdisclosure. In some aspects, the Chothia CDR-H2 sequence comprises,consists of, or consists essentially of any of the illustrative ChothiaCDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

In some aspects, the Chothia CDR-H1 sequence comprises, consists of, orconsists essentially of a variant of an illustrative Chothia CDR-H1sequence provided in this disclosure. In some aspects, the ChothiaCDR-H1 sequence comprises, consists of, or consists essentially of asequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity withany of the illustrative Chothia CDR-H1 sequences provided in thisdisclosure. In some aspects, the Chothia CDR-H1 sequence comprises,consists of, or consists essentially of any of the illustrative ChothiaCDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

2.3. V_(H) Sequences

In some embodiments, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of a sequence selected from SEQID NOs: 179-218. In some aspects, the antibody comprises a V_(H)sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 179. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 180.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 181. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 182. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 183. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 184. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 185. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 186.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 187. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 188. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 189. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 190. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 191. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 192.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 193. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 194. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 195. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 196. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 197. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 198.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 199. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 200. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 201. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 202. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 203. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 204.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 205. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 206. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 207. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 208. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 209. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 210.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 211. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 212. In some aspects, theantibody comprises a V_(H) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 213. In some aspects, the antibodycomprises a V_(H) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 214. In some aspects, the antibody comprises aV_(H) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 215. In some aspects, the antibody comprises a V_(H) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 216.In some aspects, the antibody comprises a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 217. In someaspects, the antibody comprises a V_(H) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 218.

2.3.1. Variants of V_(H) Sequences

In some embodiments, the V_(H) sequences provided herein comprise,consist of, or consist essentially of a variant of an illustrative V_(H)sequence provided in this disclosure.

In some aspects, the V_(H) sequence comprises, consists of, or consistsessentially of a variant of an illustrative V_(H) sequence provided inthis disclosure. In some aspects, the V_(H) sequence comprises, consistsof, or consists essentially of a sequence having at least 85%, 90%, 95%,96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative V_(H)sequences provided in this disclosure.

In some embodiments, the V_(H) sequence comprises, consists of, orconsists essentially of any of the illustrative V_(H) sequences providedin this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer,16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 orfewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 orfewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

2.4. CDR-L3 Sequences

In some embodiments, the antibody comprises a CDR-L3 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 141-166. In some aspects, the antibodycomprises a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 141. In some aspects, the antibody comprises aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 142. In some aspects, the antibody comprises a CDR-L3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 143. In some aspects, the antibody comprises a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 144.In some aspects, the antibody comprises a CDR-L3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 145. In someaspects, the antibody comprises a CDR-L3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 146. In some aspects, theantibody comprises a CDR-L3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 147. In some aspects, the antibodycomprises a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 148. In some aspects, the antibody comprises aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 149. In some aspects, the antibody comprises a CDR-L3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 150. In some aspects, the antibody comprises a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 151.In some aspects, the antibody comprises a CDR-L3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 152. In someaspects, the antibody comprises a CDR-L3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 153. In some aspects, theantibody comprises a CDR-L3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 154. In some aspects, the antibodycomprises a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 155. In some aspects, the antibody comprises aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 156. In some aspects, the antibody comprises a CDR-L3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 157. In some aspects, the antibody comprises a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 158.In some aspects, the antibody comprises a CDR-L3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 159. In someaspects, the antibody comprises a CDR-L3 sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 160. In some aspects, theantibody comprises a CDR-L3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 161. In some aspects, the antibodycomprises a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 162. In some aspects, the antibody comprises aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 163. In some aspects, the antibody comprises a CDR-L3sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 164. In some aspects, the antibody comprises a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 165.In some aspects, the antibody comprises a CDR-L3 sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 166.

In some aspects, the CDR-L3 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-L3 sequence provided inthis disclosure. In some aspects, the CDR-L3 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3sequences provided in this disclosure. In some aspects, the CDR-L3sequence comprises, consists of, or consists essentially of any of theillustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

2.5. V_(L) Sequences Comprising Illustrative CDRs

In some embodiments, the antibody comprises a V_(L) sequence comprisingone or more CDR-L sequences comprising, consisting of, or consistingessentially of one or more illustrative CDR-L sequences provided in thisdisclosure, and variants thereof 2.5.1. CDR-L3

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L3 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 141-166. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 141.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 142. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 143. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 144. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 145.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 146. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 147. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 148. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 149.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 150. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 151. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 152. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 153.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 154. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 155. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 156. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 157.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 158. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 159. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 160. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 161.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 162. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L3 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 163. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L3 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 164. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L3 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 165.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L3 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 166.

2.5.2. CDR-L2

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L2 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 125-140. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 125.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 126. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 127. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L2 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 128. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 129.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 130. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 131. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L2 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 132. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 133.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 134. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 135. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L2 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 136. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L2 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 137.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L2 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 138. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L2 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 139. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L2 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 140.

2.5.3. CDR-L1

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L1 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 110-124. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 110.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 111. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 112. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L1 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 113. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 114.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 115. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 116. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L1 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 117. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 118.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 119. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 120. In some aspects, the antibody comprises aV_(L) sequence comprising a CDR-L1 sequence comprising, consisting of,or consisting essentially of SEQ ID NO: 121. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 122.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 123. In some aspects, the antibody comprises a V_(L) sequencecomprising a CDR-L1 sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 124.

2.5.4. CDR-L3+CDR-L2

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L3 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 141-166 and a CDR-L2 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 125-140. In some aspects, the CDR-L3 sequenceand the CDR-L2 sequence are both from a single illustrative V_(L)sequence provided in this disclosure. For example, in some aspects, theCDR-L3 and CDR-L2 are both from a single illustrative V_(L) sequenceselected from SEQ ID NOs: 219-248.

2.5.5. CDR-L3+CDR-L1

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L3 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 141-166 and a CDR-L1 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 110-124. In some aspects, the CDR-L3 sequenceand the CDR-L1 sequence are both from a single illustrative V_(L)sequence provided in this disclosure. For example, in some aspects, theCDR-L3 and CDR-L1 are both from a single illustrative V_(L) sequenceselected from SEQ ID NOs: 219-248.

2.5.6. CDR-L1+CDR-L2

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L1 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 110-124 and a CDR-L2 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 125-140. In some aspects, the CDR-L1 sequenceand the CDR-L2 sequence are both from a single illustrative V_(L)sequence provided in this disclosure. For example, in some aspects, theCDR-L1 and CDR-L2 are both from a single illustrative V_(L) sequenceselected from SEQ ID NOs: 219-248.

2.5.7. CDR-L1+CDR-L2+CDR-L3

In some embodiments, the antibody comprises a V_(L) sequence comprisinga CDR-L1 sequence comprising, consisting of, or consisting essentiallyof a sequence selected from SEQ ID NOs: 110-124, a CDR-L2 sequencecomprising, consisting of, or consisting essentially of a sequenceselected from SEQ ID NOs: 125-140, and a CDR-L3 sequence comprising,consisting of, or consisting essentially of a sequence selected from SEQID NOs: 141-166. In some aspects, the CDR-L1 sequence, CDR-L2 sequence,and CDR-L3 sequence are all from a single illustrative V_(L) sequenceprovided in this disclosure. For example, in some aspects, the CDR-L1,CDR-L2, and CDR-L3 are all from a single illustrative V_(L) sequenceselected from SEQ ID NOs: 219-248.

In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2 sequence comprisingSEQ ID NO: 125, and a CDR-L3 sequence SEQ ID NO: 141. In some aspects,the antibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ ID NO: 126,and a CDR-L3 sequence comprising SEQ ID NO: 142. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 127,and a CDR-L3 sequence comprising sequence selected from SEQ ID NO: 142.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2 sequence comprisingSEQ ID NO: 125, and a CDR-L3 sequence comprising SEQ ID NO: 143. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 112, a CDR-L2 sequence comprising SEQ IDNO: 128, and a CDR-L3 sequence comprising SEQ ID NO: 144. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ IDNO: 126, and a CDR-L3 sequence comprising SEQ ID NO: 145. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 113, a CDR-L2 sequence comprising SEQ IDNO: 129, and a CDR-L3 sequence comprising SEQ ID NO: 146. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 114, a CDR-L2 sequence comprising SEQ IDNO: 130, and a CDR-L3 sequence comprising SEQ ID NO: 147. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 148. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 148. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 116, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 149. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 148. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 132, and a CDR-L3 sequence comprising SEQ ID NO: 149. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 117, a CDR-L2 sequence comprising SEQ IDNO: 133, and a CDR-L3 sequence comprising SEQ ID NO: 150. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 134, and a CDR-L3 sequence comprising SEQ ID NO: 148. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ IDNO: 135, and a CDR-L3 sequence comprising SEQ ID NO: 151. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ IDNO: 135, and a CDR-L3 sequence comprising SEQ ID NO: 152. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ IDNO: 136, and a CDR-L3 sequence comprising SEQ ID NO: 152. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 153. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 119, a CDR-L2 sequence comprising SEQ IDNO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 154. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ IDNO: 137, and a CDR-L3 sequence comprising SEQ ID NO: 155. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 138, and a CDR-L3 sequence comprising SEQ ID NO: 156. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 138, and a CDR-L3 sequence comprising SEQ ID NO: 157. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 122, a CDR-L2 sequence comprising SEQ IDNO: 138, and a CDR-L3 sequence comprising SEQ ID NO: 158. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 138, and a CDR-L3 sequence comprising SEQ ID NO: 159. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ IDNO: 135, and a CDR-L3 sequence comprising SEQ ID NO: 160. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 139, and a CDR-L3 sequence comprising SEQ ID NO: 161. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 123, a CDR-L2 sequence comprising SEQ IDNO: 140, and a CDR-L3 sequence comprising SEQ ID NO: 162. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 138, and a CDR-L3 sequence comprising SEQ ID NO: 163. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ IDNO: 139, and a CDR-L3 sequence comprising SEQ ID NO: 164. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ IDNO: 137, and a CDR-L3 sequence comprising SEQ ID NO: 165. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 124, a CDR-L2 sequence comprising SEQ IDNO: 125, and a CDR-L3 sequence comprising SEQ ID NO: 166.

In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2 sequence comprisingSEQ ID NO: 128, and a CDR-L3 sequence SEQ ID NO: 144. In some aspects,the antibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence comprising SEQ ID NO: 144. In some aspects, theantibody comprises a V_(L) sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 126,and a CDR-L3 sequence comprising sequence selected from SEQ ID NO: 144.In some aspects, the antibody comprises a V_(L) sequence comprising aCDR-L1 sequence comprising SEQ ID NO: 116, a CDR-L2 sequence comprisingSEQ ID NO: 131, and a CDR-L3 sequence comprising SEQ ID NO: 150. In someaspects, the antibody comprises a V_(L) sequence comprising a CDR-L1sequence comprising SEQ ID NO: 117, a CDR-L2 sequence comprising SEQ IDNO: 134, and a CDR-L3 sequence comprising SEQ ID NO: 150.

2.5.8. Variants of V_(L) Sequences Comprising Illustrative CDR-Ls

In some embodiments, the V_(L) sequences provided herein comprise avariant of an illustrative CDR-L3, CDR-L2, and/or CDR-L1 sequenceprovided in this disclosure.

In some aspects, the CDR-L3 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-L3 sequence provided inthis disclosure. In some aspects, the CDR-L3 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3sequences provided in this disclosure. In some aspects, the CDR-L3sequence comprises, consists of, or consists essentially of any of theillustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

In some aspects, the CDR-L2 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-L2 sequence provided inthis disclosure. In some aspects, the CDR-L2 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2sequences provided in this disclosure. In some aspects, the CDR-L2sequence comprises, consists of, or consists essentially of any of theillustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

In some aspects, the CDR-L1 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-L1 sequence provided inthis disclosure. In some aspects, the CDR-L1 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1sequences provided in this disclosure. In some aspects, the CDR-L1sequence comprises, consists of, or consists essentially of any of theillustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

2.6. V_(L) Sequences

In some embodiments, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of a sequence selected from SEQID NOs: 219-248. In some aspects, the antibody comprises a V_(L)sequence comprising, consisting of, or consisting essentially of SEQ IDNO: 219. In some aspects, the antibody comprises a V_(L) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 220.In some aspects, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 221. In someaspects, the antibody comprises a V_(L) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 222. In some aspects, theantibody comprises a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 223. In some aspects, the antibodycomprises a V_(L) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 224. In some aspects, the antibody comprises aV_(L) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 225. In some aspects, the antibody comprises a V_(L) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 226.In some aspects, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 227. In someaspects, the antibody comprises a V_(L) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 228. In some aspects, theantibody comprises a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 229. In some aspects, the antibodycomprises a V_(L) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 230. In some aspects, the antibody comprises aV_(L) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 231. In some aspects, the antibody comprises a V_(L) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 232.In some aspects, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 233. In someaspects, the antibody comprises a V_(L) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 234. In some aspects, theantibody comprises a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 235. In some aspects, the antibodycomprises a V_(L) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 236. In some aspects, the antibody comprises aV_(L) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 237. In some aspects, the antibody comprises a V_(L) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 238.In some aspects, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 239. In someaspects, the antibody comprises a V_(L) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 240. In some aspects, theantibody comprises a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 241. In some aspects, the antibodycomprises a V_(L) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 242. In some aspects, the antibody comprises aV_(L) sequence comprising, consisting of, or consisting essentially ofSEQ ID NO: 243. In some aspects, the antibody comprises a V_(L) sequencecomprising, consisting of, or consisting essentially of SEQ ID NO: 244.In some aspects, the antibody comprises a V_(L) sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 245. In someaspects, the antibody comprises a V_(L) sequence comprising, consistingof, or consisting essentially of SEQ ID NO: 246. In some aspects, theantibody comprises a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NO: 247. In some aspects, the antibodycomprises a V_(L) sequence comprising, consisting of, or consistingessentially of SEQ ID NO: 248.

2.6.1. Variants of V_(L) Sequences

In some embodiments, the V_(L) sequences provided herein comprise,consist of, or consist essentially of a variant of an illustrative V_(L)sequence provided in this disclosure.

In some aspects, the V_(L) sequence comprises, consists of, or consistsessentially of a variant of an illustrative V_(L) sequence provided inthis disclosure. In some aspects, the V_(L) sequence comprises, consistsof, or consists essentially of a sequence having at least 85%, 90%, 95%,96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrativeV_(L) sequences provided in this disclosure.

In some embodiments, the V_(L) sequence comprises, consists of, orconsists essentially of any of the illustrative V_(L) sequences providedin this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer,16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 orfewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 orfewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

2.7. Pairs 2.7.1. CDR-H3-CDR-L3 Pairs

In some embodiments, the antibody comprises a CDR-H3 sequence and aCDR-L3 sequence. In some aspects, the CDR-H3 sequence is part of a V_(H)and the CDR-L3 sequence is part of a VL.

In some aspects, the CDR-H3 sequence is a CDR-H3 sequence comprising,consisting of, or consisting essentially of SEQ ID NOs: 82-109, and theCDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, orconsisting essentially of SEQ ID NOs: 141-166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 82 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 83 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 84 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 85 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 86 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 87 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 88 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 89 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 90 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 91 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 92 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 93 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 94 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 95 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 96 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 97 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 98 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 99 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 100 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 101 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 102 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 103 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 104 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 105 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 106 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 107 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 108 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

In some aspects, the CDR-H3 sequence is SEQ ID NO: 109 and the CDR-L3sequence is selected from SEQ ID NOs: 141-166. In some aspects, theCDR-L3 sequence is SEQ ID NO: 141. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 142. In some aspects, the CDR-L3 sequence is SEQ ID NO:143. In some aspects, the CDR-L3 sequence is SEQ ID NO: 144. In someaspects, the CDR-L3 sequence is SEQ ID NO: 145. In some aspects, theCDR-L3 sequence is SEQ ID NO: 146. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 147. In some aspects, the CDR-L3 sequence is SEQ ID NO:148. In some aspects, the CDR-L3 sequence is SEQ ID NO: 149. In someaspects, the CDR-L3 sequence is SEQ ID NO: 150. In some aspects, theCDR-L3 sequence is SEQ ID NO: 151. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 152. In some aspects, the CDR-L3 sequence is SEQ ID NO:153. In some aspects, the CDR-L3 sequence is SEQ ID NO: 154. In someaspects, the CDR-L3 sequence is SEQ ID NO: 155. In some aspects, theCDR-L3 sequence is SEQ ID NO: 156. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 157. In some aspects, the CDR-L3 sequence is SEQ ID NO:158. In some aspects, the CDR-L3 sequence is SEQ ID NO: 159. In someaspects, the CDR-L3 sequence is SEQ ID NO: 160. In some aspects, theCDR-L3 sequence is SEQ ID NO: 161. In some aspects, the CDR-L3 sequenceis SEQ ID NO: 162. In some aspects, the CDR-L3 sequence is SEQ ID NO:163. In some aspects, the CDR-L3 sequence is SEQ ID NO: 164. In someaspects, the CDR-L3 sequence is SEQ ID NO: 165. In some aspects, theCDR-L3 sequence is SEQ ID NO: 166.

2.7.1.1. Variants of CDR-H3-CDR-L3 Pairs

In some embodiments, the CDR-H3-CDR-L3 pairs provided herein comprise avariant of an illustrative CDR-H3 and/or CDR-L1 sequence provided inthis disclosure.

In some aspects, the CDR-H3 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-H3 sequence provided inthis disclosure. In some aspects, the CDR-H3 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3sequences provided in this disclosure. In some aspects, the CDR-H3sequence comprises, consists of, or consists essentially of any of theillustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

In some aspects, the CDR-L3 sequence comprises, consists of, or consistsessentially of a variant of an illustrative CDR-L3 sequence provided inthis disclosure. In some aspects, the CDR-L3 sequence comprises,consists of, or consists essentially of a sequence having at least 70%,75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3sequences provided in this disclosure. In some aspects, the CDR-L3sequence comprises, consists of, or consists essentially of any of theillustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or3 amino acid substitutions. In some aspects, the amino acidsubstitutions are conservative amino acid substitutions.

2.7.2. V_(H)-V_(L) Pairs

In some embodiments, the antibody comprises a V_(H) sequence and a V_(L)sequence.

In some aspects, the V_(H) sequence is a V_(H) sequence comprising,consisting of, or consisting essentially of SEQ ID NOs: 179-218 and theV_(L) sequence is a V_(L) sequence comprising, consisting of, orconsisting essentially of SEQ ID NOs: 219-248.

In some aspects, the V_(H) sequence is SEQ ID NO: 179 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 180 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 181 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 182 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 183 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 184 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 185 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 186 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 187 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 188 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 189 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 190 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 191 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 192 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 193 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 194 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 195 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 196 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 197 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 198 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 199 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 200 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 201 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 202 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 203 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 204 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 205 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 206 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 207 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 208 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 209 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 210 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 211 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 212 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 213 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 214 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 215 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 216 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 217 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

In some aspects, the V_(H) sequence is SEQ ID NO: 218 and the V_(L)sequence is selected from SEQ ID NOs: 219-248. In some aspects, theV_(L) sequence is SEQ ID NO: 219. In some aspects, the V_(L) sequence isSEQ ID NO: 220. In some aspects, the V_(L) sequence is SEQ ID NO: 221.In some aspects, the V_(L) sequence is SEQ ID NO: 222. In some aspects,the V_(L) sequence is SEQ ID NO: 223. In some aspects, the V_(L)sequence is SEQ ID NO: 224. In some aspects, the V_(L) sequence is SEQID NO: 225. In some aspects, the V_(L) sequence is SEQ ID NO: 226. Insome aspects, the V_(L) sequence is SEQ ID NO: 227. In some aspects, theV_(L) sequence is SEQ ID NO: 228. In some aspects, the V_(L) sequence isSEQ ID NO: 229. In some aspects, the V_(L) sequence is SEQ ID NO: 230.In some aspects, the V_(L) sequence is SEQ ID NO: 231. In some aspects,the V_(L) sequence is SEQ ID NO: 232. In some aspects, the V_(L)sequence is SEQ ID NO: 233. In some aspects, the V_(L) sequence is SEQID NO: 234. In some aspects, the V_(L) sequence is SEQ ID NO: 235. Insome aspects, the V_(L) sequence is SEQ ID NO: 236. In some aspects, theV_(L) sequence is SEQ ID NO: 237. In some aspects, the V_(L) sequence isSEQ ID NO: 238. In some aspects, the V_(L) sequence is SEQ ID NO: 239.In some aspects, the V_(L) sequence is SEQ ID NO: 240. In some aspects,the V_(L) sequence is SEQ ID NO: 241. In some aspects, the V_(L)sequence is SEQ ID NO: 242. In some aspects, the V_(L) sequence is SEQID NO: 243. In some aspects, the V_(L) sequence is SEQ ID NO: 244. Insome aspects, the V_(L) sequence is SEQ ID NO: 245. In some aspects, theV_(L) sequence is SEQ ID NO: 246. In some aspects, the V_(L) sequence isSEQ ID NO: 247. In some aspects, the V_(L) sequence is SEQ ID NO: 248.

2.7.3. CDR-H1+CDR-H2+CDR-H3+CDR-L1+CDR-L2+CDR-L3

In some aspects, the antibody comprises a V_(H) sequence comprising aKabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2 sequencecomprising SEQ ID NO: 63, and a Kabat CDR-H3 sequence comprising SEQ IDNO: 82 and a VL sequence comprising a CDR-L1 sequence comprising SEQ IDNO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3sequence SEQ ID NO: 141. In some aspects, the antibody comprises a V_(H)sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, aKabat CDR-H2 sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3sequence comprising SEQ ID NO: 83 and a VL sequence comprising a CDR-L1sequence comprising SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ IDNO: 126, and a CDR-L3 sequence SEQ ID NO: 142. In some aspects, theantibody comprises a V_(H) sequence comprising a Kabat CDR-H1 sequencecomprising SEQ ID NO: 27, a Kabat CDR-H2 sequence comprising SEQ ID NO:65, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 84 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 110, aCDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ IDNO: 141. In some aspects, the antibody comprises a V_(H) sequencecomprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a KabatCDR-H2 sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 85 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 141. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 64, and aKabat CDR-H3 sequence comprising SEQ ID NO: 86 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2sequence comprising SEQ ID NO: 127, and a CDR-L3 sequence SEQ ID NO:142. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 25, a Kabat CDR-H2sequence comprising SEQ ID NO: 66, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 141. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 26, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and aKabat CDR-H3 sequence comprising SEQ ID NO: 82 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 110, a CDR-L2sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ ID NO:143. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2sequence comprising SEQ ID NO: 65, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 112, a CDR-L2 sequence comprising SEQ ID NO: 128,and a CDR-L3 sequence SEQ ID NO: 144. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 27, a Kabat CDR-H2 sequence comprising SEQ ID NO: 65, and aKabat CDR-H3 sequence comprising SEQ ID NO: 82 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 111, a CDR-L2sequence comprising SEQ ID NO: 126, and a CDR-L3 sequence SEQ ID NO:145. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 28, a Kabat CDR-H2sequence comprising SEQ ID NO: 67, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 113, a CDR-L2 sequence comprising SEQ ID NO: 129,and a CDR-L3 sequence SEQ ID NO: 146. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 29, a Kabat CDR-H2 sequence comprising SEQ ID NO: 68, and aKabat CDR-H3 sequence comprising SEQ ID NO: 82 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 114, a CDR-L2sequence comprising SEQ ID NO: 130, and a CDR-L3 sequence SEQ ID NO:147. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 26, a Kabat CDR-H2sequence comprising SEQ ID NO: 64, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 141. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 30, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 87 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:148. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 31, a Kabat CDR-H2sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 88 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 116, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 32, a Kabat CDR-H2 sequence comprising SEQ ID NO: 71, and aKabat CDR-H3 sequence comprising SEQ ID NO: 89 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:148. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 33, a Kabat CDR-H2sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 90 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 132,and a CDR-L3 sequence SEQ ID NO: 149. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 34, a Kabat CDR-H2 sequence comprising SEQ ID NO: 72, and aKabat CDR-H3 sequence comprising SEQ ID NO: 91 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:148. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a Kabat CDR-H2sequence comprising SEQ ID NO: 71, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 92 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 35, a Kabat CDR-H2 sequence comprising SEQ ID NO: 70, and aKabat CDR-H3 sequence comprising SEQ ID NO: 93 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 117, a CDR-L2sequence comprising SEQ ID NO: 133, and a CDR-L3 sequence SEQ ID NO:150. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 33, a Kabat CDR-H2sequence comprising SEQ ID NO: 70, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 92 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 134,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 36, a Kabat CDR-H2 sequence comprising SEQ ID NO: 72, and aKabat CDR-H3 sequence comprising SEQ ID NO: 87 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:148. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 30, a Kabat CDR-H2sequence comprising SEQ ID NO: 73, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 87 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 37, a Kabat CDR-H2 sequence comprising SEQ ID NO: 74, and aKabat CDR-H3 sequence comprising SEQ ID NO: 87 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 115, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:148. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 94 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 135,and a CDR-L3 sequence SEQ ID NO: 151. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 39, a Kabat CDR-H2 sequence comprising SEQ ID NO: 76, and aKabat CDR-H3 sequence comprising SEQ ID NO: 95 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR-L2sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO:152. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 40, a Kabat CDR-H2sequence comprising SEQ ID NO: 76, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 96 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 136,and a CDR-L3 sequence SEQ ID NO: 152. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 39, a Kabat CDR-H2 sequence comprising SEQ ID NO: 76, and aKabat CDR-H3 sequence comprising SEQ ID NO: 94 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR-L2sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO:152. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 97 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 153. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 41, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 98 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 119, a CDR-L2sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ ID NO:154. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 41, a Kabat CDR-H2sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 99 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ ID NO: 137,and a CDR-L3 sequence SEQ ID NO: 155. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 41, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 100 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 121, a CDR-L2sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ ID NO:156. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 101 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 138,and a CDR-L3 sequence SEQ ID NO: 157. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 42, a Kabat CDR-H2 sequence comprising SEQ ID NO: 78, and aKabat CDR-H3 sequence comprising SEQ ID NO: 102 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 122, a CDR-L2sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ ID NO:158. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 103 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 138,and a CDR-L3 sequence SEQ ID NO: 159. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 43, a Kabat CDR-H2 sequence comprising SEQ ID NO: 79, and aKabat CDR-H3 sequence comprising SEQ ID NO: 104 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 118, a CDR-L2sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ ID NO:160. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 75, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 103 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 139,and a CDR-L3 sequence SEQ ID NO: 161. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 38, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 105 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 123, a CDR-L2sequence comprising SEQ ID NO: 140, and a CDR-L3 sequence SEQ ID NO:162. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 38, a Kabat CDR-H2sequence comprising SEQ ID NO: 69, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 106 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 138,and a CDR-L3 sequence SEQ ID NO: 163. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 38, a Kabat CDR-H2 sequence comprising SEQ ID NO: 69, and aKabat CDR-H3 sequence comprising SEQ ID NO: 107 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 121, a CDR-L2sequence comprising SEQ ID NO: 139, and a CDR-L3 sequence SEQ ID NO:164. In some aspects, the antibody comprises a V_(H) sequence comprisinga Kabat CDR-H1 sequence comprising SEQ ID NO: 44, a Kabat CDR-H2sequence comprising SEQ ID NO: 80, and a Kabat CDR-H3 sequencecomprising SEQ ID NO: 108 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 120, a CDR-L2 sequence comprising SEQ ID NO: 137,and a CDR-L3 sequence SEQ ID NO: 165. In some aspects, the antibodycomprises a V_(H) sequence comprising a Kabat CDR-H1 sequence comprisingSEQ ID NO: 45, a Kabat CDR-H2 sequence comprising SEQ ID NO: 81, and aKabat CDR-H3 sequence comprising SEQ ID NO: 109 and a VL sequencecomprising a CDR-L1 sequence comprising SEQ ID NO: 124, a CDR-L2sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ ID NO:166.

In some aspects, the antibody comprises a V_(H) sequence comprising aChothia CDR-H1 sequence comprising SEQ ID NO: 1, a Chothia CDR-H2sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 141. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 83 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 111, aCDR-L2 sequence comprising SEQ ID NO: 126, and a CDR-L3 sequence SEQ IDNO: 142. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 84 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 141. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 85 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 110, aCDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ IDNO: 141. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 3, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 47, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 86 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 127,and a CDR-L3 sequence SEQ ID NO: 142. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 4, a Chothia CDR-H2 sequence comprising SEQ ID NO:46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 110, aCDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ IDNO: 141. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 2, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 110, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 143. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:46, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 112, aCDR-L2 sequence comprising SEQ ID NO: 128, and a CDR-L3 sequence SEQ IDNO: 144. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 1, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 46, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 111, a CDR-L2 sequence comprising SEQ ID NO: 126,and a CDR-L3 sequence SEQ ID NO: 145. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 5, a Chothia CDR-H2 sequence comprising SEQ ID NO:49, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 113, aCDR-L2 sequence comprising SEQ ID NO: 129, and a CDR-L3 sequence SEQ IDNO: 146. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 6, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 50, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 82 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 114, a CDR-L2 sequence comprising SEQ ID NO: 130,and a CDR-L3 sequence SEQ ID NO: 147. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 2, a Chothia CDR-H2 sequence comprising SEQ ID NO:47, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 82 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 110, aCDR-L2 sequence comprising SEQ ID NO: 125, and a CDR-L3 sequence SEQ IDNO: 141. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 7, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 8, a Chothia CDR-H2 sequence comprising SEQ ID NO:52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 88 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 116, aCDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ IDNO: 149. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 9, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 53, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 89 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprising SEQ IDNO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 90 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, aCDR-L2 sequence comprising SEQ ID NO: 132, and a CDR-L3 sequence SEQ IDNO: 149. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 11, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 54, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 91 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 12, a Chothia CDR-H2 sequence comprising SEQ IDNO: 53, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 92 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, aCDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ IDNO: 148. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 13, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 93 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 117, a CDR-L2 sequence comprising SEQ ID NO: 133,and a CDR-L3 sequence SEQ ID NO: 150. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 10, a Chothia CDR-H2 sequence comprising SEQ IDNO: 52, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 92 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, aCDR-L2 sequence comprising SEQ ID NO: 134, and a CDR-L3 sequence SEQ IDNO: 148. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 54, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 15, a Chothia CDR-H2 sequence comprising SEQ IDNO: 55, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 87 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, aCDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ IDNO: 148. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 56, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 87 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 115, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 148. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 94 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 118, aCDR-L2 sequence comprising SEQ ID NO: 135, and a CDR-L3 sequence SEQ IDNO: 151. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 18, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 57, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 95 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 135and a CDR-L3 sequence SEQ ID NO: 152. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 19, a Chothia CDR-H2 sequence comprising SEQ IDNO: 57, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 96 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 118, aCDR-L2 sequence comprising SEQ ID NO: 136, and a CDR-L3 sequence SEQ IDNO: 152. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 21, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 57, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 94 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 135,and a CDR-L3 sequence SEQ ID NO: 152. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 97 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 115, aCDR-L2 sequence comprising SEQ ID NO: 131, and a CDR-L3 sequence SEQ IDNO: 153. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 22, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 52, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 98 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 119, a CDR-L2 sequence comprising SEQ ID NO: 131,and a CDR-L3 sequence SEQ ID NO: 154. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 22, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 99 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 120, aCDR-L2 sequence comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ IDNO: 155. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 22, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 100 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 138,and a CDR-L3 sequence SEQ ID NO: 156. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 101 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 121, aCDR-L2 sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ IDNO: 157. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 59, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 102 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 122, a CDR-L2 sequence comprising SEQ ID NO: 138,and a CDR-L3 sequence SEQ ID NO: 158. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 103 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 121, aCDR-L2 sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ IDNO: 159. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 23, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 60, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 104 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 118, a CDR-L2 sequence comprising SEQ ID NO: 135,and a CDR-L3 sequence SEQ ID NO: 160. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 103 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 121, aCDR-L2 sequence comprising SEQ ID NO: 139, and a CDR-L3 sequence SEQ IDNO: 161. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 105 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 123, a CDR-L2 sequence comprising SEQ ID NO: 140,and a CDR-L3 sequence SEQ ID NO: 162. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 51, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 106 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 121, aCDR-L2 sequence comprising SEQ ID NO: 138, and a CDR-L3 sequence SEQ IDNO: 163. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 51, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 107 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 121, a CDR-L2 sequence comprising SEQ ID NO: 139,and a CDR-L3 sequence SEQ ID NO: 164. In some aspects, the antibodycomprises a V_(H) sequence comprising a Chothia CDR-H1 sequencecomprising SEQ ID NO: 17, a Chothia CDR-H2 sequence comprising SEQ IDNO: 61, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 108 and a VLsequence comprising a CDR-L1 sequence comprising SEQ ID NO: 120, aCDR-L2 sequence comprising SEQ ID NO: 137, and a CDR-L3 sequence SEQ IDNO: 165. In some aspects, the antibody comprises a V_(H) sequencecomprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 17, a ChothiaCDR-H2 sequence comprising SEQ ID NO: 62, and a Chothia CDR-H3 sequencecomprising SEQ ID NO: 109 and a VL sequence comprising a CDR-L1 sequencecomprising SEQ ID NO: 124, a CDR-L2 sequence comprising SEQ ID NO: 125,and a CDR-L3 sequence SEQ ID NO: 166.

2.7.3.1. Variants of V_(H)-V_(L) Pairs

In some embodiments, the V_(H)-V_(L) pairs provided herein comprise avariant of an illustrative V_(H) and/or V_(L) sequence provided in thisdisclosure.

In some aspects, the V_(H) sequence comprises, consists of, or consistsessentially of a variant of an illustrative V_(H) sequence provided inthis disclosure. In some aspects, the V_(H) sequence comprises, consistsof, or consists essentially of a sequence having at least 85%, 90%, 95%,96%, 97%, 98%, 99%, or 99.1% identity with any of the illustrative V_(H)sequences provided in this disclosure.

In some embodiments, the V_(H) sequence comprises, consists of, orconsists essentially of any of the illustrative V_(H) sequences providedin this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer,16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 orfewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 orfewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

In some aspects, the V_(L) sequence comprises, consists of, or consistsessentially of a variant of an illustrative V_(L) sequence provided inthis disclosure. In some aspects, the V_(L) sequence comprises, consistsof, or consists essentially of a sequence having at least 85%, 90%, 95%,96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrativeV_(L) sequences provided in this disclosure.

In some embodiments, the V_(L) sequence comprises, consists of, orconsists essentially of any of the illustrative V_(L) sequences providedin this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer,16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 orfewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 orfewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acidsubstitutions. In some aspects, the amino acid substitutions areconservative amino acid substitutions.

2.7.4 HC+LC

In some embodiments, the antibody comprises or consists of one or moreheavy chains consisting of an HC sequence and one or more light chainsconsisting of an LC sequence. In some embodiments, the antibodycomprises or consists of two identical heavy chains consisting of an HCsequence and two identical light chains consisting of an LC sequence.

In some embodiments, the HC sequence is an HC sequence comprising,consisting of, or consisting essentially of SEQ ID NO: 255, SEQ ID NO:257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 263, SEQ ID NO: 265, SEQID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO: 273, SEQ ID NO:275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQ ID NO: 283, SEQID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO: 291, SEQ ID NO:293, SEQ ID NO: 295, or SEQ ID NO: 297 and the LC sequence is a LCsequence comprising, consisting of, or consisting essentially of SEQ IDNO: 256, SEQ ID NO: 258, SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264,SEQ ID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ IDNO: 274, SEQ ID NO: 276, SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282,SEQ ID NO: 284, SEQ ID NO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ IDNO: 292, SEQ ID NO: 294, SEQ ID NO: 296, or SEQ ID NO: 298. In someembodiments, the HC sequence is an HC sequence consisting of SEQ ID NO:255, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 263, SEQID NO: 265, SEQ ID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO:273, SEQ ID NO: 275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO:291, SEQ ID NO: 293, SEQ ID NO: 295, or SEQ ID NO: 297 and the LCsequence is an LC sequence consisting of SEQ ID NO: 256, SEQ ID NO: 258,SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264, SEQ ID NO: 266, SEQ IDNO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ ID NO: 274, SEQ ID NO: 276,SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282, SEQ ID NO: 284, SEQ IDNO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ ID NO: 292, SEQ ID NO: 294,SEQ ID NO: 296, or SEQ ID NO: 298.

In some embodiments, the HC sequence is an HC sequence consisting of SEQID NO: 255 and the LC sequence is an LC sequence consisting of SEQ IDNO: 256. In some embodiments, the HC sequence is an HC sequenceconsisting of SEQ ID NO: 257 and the LC sequence is an LC sequenceconsisting of SEQ ID NO: 258. In some embodiments, the HC sequence is anHC sequence consisting of SEQ ID NO: 259 and the LC sequence is an LCsequence consisting of SEQ ID NO: 260. In some embodiments, the HCsequence is an HC sequence consisting of SEQ ID NO: 261 and the LCsequence is an LC sequence consisting of SEQ ID NO: 262. In someembodiments, the HC sequence is an HC sequence consisting of SEQ ID NO:263 and the LC sequence is an LC sequence consisting of SEQ ID NO: 264.In some embodiments, the HC sequence is an HC sequence consisting of SEQID NO: 265 and the LC sequence is an LC sequence consisting of SEQ IDNO: 266. In some embodiments, the HC sequence is an HC sequenceconsisting of SEQ ID NO: 267 and the LC sequence is an LC sequenceconsisting of SEQ ID NO: 268. In some embodiments, the HC sequence is anHC sequence consisting of SEQ ID NO: 269 and the LC sequence is an LCsequence consisting of SEQ ID NO: 270. In some embodiments, the HCsequence is an HC sequence consisting of SEQ ID NO: 271 and the LCsequence is an LC sequence consisting of SEQ ID NO: 272. In someembodiments, the HC sequence is an HC sequence consisting of SEQ ID NO:273 and the LC sequence is an LC sequence consisting of SEQ ID NO: 274.In some embodiments, the HC sequence is an HC sequence consisting of SEQID NO: 275 and the LC sequence is an LC sequence consisting of SEQ IDNO: 276. In some embodiments, the HC sequence is an HC sequenceconsisting of SEQ ID NO: 277 and the LC sequence is an LC sequenceconsisting of SEQ ID NO: 278. In some embodiments, the HC sequence is anHC sequence consisting of SEQ ID NO: 279 and the LC sequence is an LCsequence consisting of SEQ ID NO: 280. In some embodiments, the HCsequence is an HC sequence consisting of SEQ ID NO: 281 and the LCsequence is an LC sequence consisting of SEQ ID NO: 282. In someembodiments, the HC sequence is an HC sequence consisting of SEQ ID NO:283 and the LC sequence is an LC sequence consisting of SEQ ID NO: 284.In some embodiments, the HC sequence is an HC sequence consisting of SEQID NO: 285 and the LC sequence is an LC sequence consisting of SEQ IDNO: 286. In some embodiments, the HC sequence is an HC sequenceconsisting of SEQ ID NO: 287 and the LC sequence is an LC sequenceconsisting of SEQ ID NO: 288. In some embodiments, the HC sequence is anHC sequence consisting of SEQ ID NO: 289 and the LC sequence is an LCsequence consisting of SEQ ID NO: 290. In some embodiments, the HCsequence is an HC sequence consisting of SEQ ID NO: 291 and the LCsequence is an LC sequence consisting of SEQ ID NO: 292. In someembodiments, the HC sequence is an HC sequence consisting of SEQ ID NO:293 and the LC sequence is an LC sequence consisting of SEQ ID NO: 294.In some embodiments, the HC sequence is an HC sequence consisting of SEQID NO: 295 and the LC sequence is an LC sequence consisting of SEQ IDNO: 296. In some embodiments, the HC sequence is an HC sequenceconsisting of SEQ ID NO: 297 and the LC sequence is an LC sequenceconsisting of SEQ ID NO: 298.

2.8. Consensus Sequences

In some embodiments, provided herein are anti-CD39 antibodies comprisingone or more sequences defined by consensus sequences. Each consensussequence is based, at least in part, on one or more alignments of two ormore useful anti-CD39 CDR sequences provided in this disclosure. Basedon such alignments, a person of skill in the art would recognize thatdifferent amino acid residues may useful in certain positions of theCDRs. Accordingly, each consensus sequence encompasses two or moreuseful anti-CD39 CDR sequences.

2.8.1. CDR-H3 Consensus Sequences

In some embodiments, the antibody comprises a CDR-H3 sequence defined bythe consensus sequence G-K-R-E-G-G-T-E-Y-L-R-γ₁₂ (SEQ ID NOS: 82-86),where γ₁₂ is H, K, S, N, or V.

In some aspects, γ₁₂ is H. In some aspects, γ₁₂ is K In some aspects,γ₁₂ is S. In some aspects, γ₁₂ is N. In some aspects, γ₁₂ is V.

In some embodiments, the antibody comprises a CDR-H3 sequence defined bythe consensus sequence E-S-G-Φ₄-Y-R-D-H-R-L-Φ₁₁-V (SEQ ID NOS: 94-96),where Φ₄ is G or T and Φ₁₁ is D or G.

In some aspects, Φ₄ is G when Φ₁₁ is D or G. In some aspects, Φ₁₁ is Dwhen Φ₄ is G or T.

In some aspects, Φ₄ is G and Φ₁₁ is D. In some aspects, Φ₄ is T and Φ₁₁is D. In some aspects, Φ₄ is G and Φ₁₁ is G.

In some embodiments, the antibody comprises a CDR-H3 sequence defined bythe consensus sequence G-G-A-K-Y-A-

₇-

₈-

₉-G-M-D-V (SEQ ID NOS: 87-93), where

₇ is S, V, G, or R;

₈ is T, Q, K, G, or R; and

₉ is Y, H, L, or W.

In some aspects,

₇ is S when

₅ is T, Q, or K and

₉ is Y, H, L, or W. In some aspects,

₈ is T when

₇ is S or R and

₉ is Y or H. In some aspects,

₉ is Y when

₇ is S, V, G, or R and

₈ is T, G, or R.

In some aspects,

₇ is S when

₈ is T and

₉ is Y. In some aspects,

₇ is S when

₈ is T and

₉ is H. In some aspects,

₇ is S when

₈ is Q and

₉ is L. In some aspects,

₇ is S when

₈ is K and

₉ is W. In some aspects,

₇ is V when

₈ is G and

₉ is Y. In some aspects,

₇ is G when

₈ is R and

₉ is Y. In some aspects,

₇ is R when

₈ is T and

₉ is Y.

2.8.2. Chothia CDR-H2 Consensus Sequences

In some embodiments, the antibody comprises a Chothia CDR-H2 sequencedefined by the consensus sequence N-P-ε₅-ε₆-G-S-T (SEQ ID NOS: 46-48),where ε₅ is L, R, or S and ε₆ is G or V.

In some aspects, when ε₅ is S, ε₆ is G or V. In some aspects, when ε₆ isG, ε₅ is S, L, or R.

In some aspects, when ε₅ is L, ε₆ is G. In some aspects, when ε₅ is S,ε₆ is G. In some aspects, when ε₅ is S, ε₆ is V. In some aspects, whenε₅ is R, ε₆ is G.

In some embodiments, the antibody comprises a Chothia CDR-H2 sequencedefined by the consensus sequence α₃-α₄-α₅-α₆-G-T-A (SEQ ID NOS: 51-54),where α₃ is I or L or is absent; α₄ is P or is absent; and as is I, G,or R; and α₆ is A, F, or G.

In some aspects, when α₃, is I, α₄ is P; as is I or R; and α₆ is F or G.In some aspects, when α₃, is L, α₄ is P; as is I; and α₆ is A or G. Insome aspects, when α₄, is P, α₃ is I or L; as is I or R; and α₆ is A, F,or G. In some aspects, when as, is I, α₃ is I or L; α₄ is P; and α₆ isA, F, or G. In some aspects, when α₆, is F, α₃ is I or is absent; α₄ isP or is absent; and as is I or G. In some aspects, when α₆, is G, α₃ isI or L; α₄ is P; and as is I or R.

In some aspects, when α₃ is L, α₄ is P; as is I; and α₆ is A. In someaspects, when α₃ is I, α₄ is P; as is I; and α₆ is F. In some aspects,when α₃ is absent, α₄ is absent; as is G; and α₆ is F. In some aspects,when α₃ is L, α₄ is P; as is I; and α₆ is G. In some aspects, when α₃ isI, α₄ is P; as is R; and α₆ is G.

In some embodiments, the antibody comprises a Chothia CDR-H2 sequencedefined by the consensus sequence I-P-β₅-β₆-G-β₈-A (SEQ ID NOS: 56-60),where β₅ is I, E, S, or T; β₆ is F, I, or S; and β₈ is I or T.

In some aspects, when β₅ is I, β₆ is F or S and β₈ is T. In someaspects, when β₆ is F, β₅ is E, I, or T and β₈ is I or T. In someaspects, when β₈ is T, β₅ is I, S, or T and β₆ is F, I, or S.

In some aspects, when β₅ is I, β₆ is F and β₈ is T. In some aspects,when β₅ is E, β₆ is F and β₈ is I. In some aspects, when β₅ is S, β₆ isI and β₈ is T. In some aspects, when β₅ is I, β₆ is S and β₈ is T. Insome aspects, when β₅ is T, β₆ is S and β₈ is T.

2.8.3. Chothia CDR-H1 Consensus Sequences

In some embodiments, the antibody comprises a Chothia CDR-H1 sequencedefined by the consensus sequence G-Y-T-F-Ω₅-S-Y (SEQ ID NOS: 1-2 and4-6), where Ω₅ is T, K, Q, F, or V.

In some aspects, Ω₅ is T. In some aspects, Ω₅ is K. In some aspects, Ω₅is Q. In some aspects, Ω₅ is F. In some aspects, Ω₅ is V.

In some embodiments, the antibody comprises a Chothia CDR-H1 sequencedefined by the consensus sequence G-G-T-F-ν₅-ν₆-Y (SEQ ID NOS: 17-22 and24), where ν₅ is S, G, or E and ν₆ is S, K, R, or S.

In some aspects, ν₅ is S when ν₆ is S or K. In some aspects, ν₆ is Swhen ν₅ is S or E.

In some aspects, ν₅ is S when ν₆ is S. In some embodiments, ν₅ is S whenν₆ is K. In some aspects, ν₅ is G when ν₆ is R. In some aspects ν₅ is Ewhen ν₆ is S.

In some embodiments, the antibody comprises a Chothia CDR-H1 sequencedefined by the consensus sequence G-G-T-F-κ₅-κ₆-κ₇ (SEQ ID NOS: 7-16),where κ₅ is S, Q, P, or A; κ₆ is S, K, H, L, A, or W; and κ₇ is Y, L, T,N, or M.

In some aspects, when κ₅ is S, κ₆ is S, K, H, L, A, or W and κ₇ is Y, L,T, or M. In some aspects, when κ₆ is S, κ₅ is S, Q, P, or A and κ₇ is Y,L, or N. In some aspects, when κ₇ is L, κ₅ is S, Q, or A and κ₆ is S, K,L, or W.

In some aspects, when κ₅ is S, κ₆ is S and κ₇ is Y. In some aspects,when κ₅ is S, κ₆ is S and κ₇ is L. In some aspects, when κ₅ is S, κ₆ isK and κ₇ is L. In some aspects, when κ₅ is S, κ₆ is H and κ₇ is T. Insome aspects, when κ₅ is S, κ₆ is L and κ₇ is L. In some aspects, whenκ₅ is Q, κ₆ is S and κ₇ is L. In some aspects, when κ₅ is P, κ₆ is S andκ₇ is N. In some aspects, when κ₅ is S, κ₆ is A and κ₇ is M. In someaspects, when κ₅ is A, κ₆ is S and κ₇ is L. In some aspects, when κ₅ isS, κ6 is W and κ₇ is L.

2.8.4. Kabat CDR-H2 Consensus Sequences

In some embodiments, the antibody comprises a Kabat CDR-H2 sequencedefined by the consensus sequence ε₁-I-N-P-ε₅-ε₆-G-S-T-ε₁₀-Y-A-Q-K-F-Q-G(SEQ ID NOS: 63-66 and 68), where ε₁ is K, S, R, or V; ε₅ is L, R, or S;ε₆ is G or V; and ε₁₀ is S or W.

In some aspects, when ε₁ is V; ε₅ is L or S; ε₆ is G; and ε₁₀ is S. Insome aspects, when ε₁ is R; ε₅ is S; ε₆ is V or G; and ε₁₀ is W. In someaspects, when ε₅ is S; ε₁ is R or V; ε₆ is G or V; and ε₁₀ is S or W. Insome aspects, when ε₆ is G; ε₁ is R or V; ε₅ is S; and ε₁₀ is S or W. Insome aspects, when ε₁₀ is S; ε₁ is V or S; ε₅ is L, R, or S; and ε₆ isG. In some aspects, when ε₁₀ is W; ε₁ is K or R; ε₅ is S; and ε₆ is G orV.

In some aspects, when ε₁ is V; ε₅ is L; ε₆ is G; and ε₁₀ is S. In someaspects, when ε₁ is V; ε₅ is S; ε₆ is G; and ε₁₀ is S. In some aspects,when ε₁ is R; ε₅ is S; ε₆ is V; and ε₁₀ is W. In some aspects, when ε₁is R; ε₅ is S; ε₆ is G; and ε₁₀ is W. In some aspects, when ε₁ is K; ε₅is S; ε₆ is G; and ε₁₀ is W. In some aspects, when ε₁ is S; ε₅ is R; ε₆is G; and ε₁₀ is S.

In some embodiments, the antibody comprises a Kabat CDR-H2 sequencedefined by the consensus sequence G-I-α₃-α₄-as-α₆-G-T-A-N-Y-A-Q-K-F-Q-G(SEQ ID NOS: 69-72), where α₃ is I or L or is absent; α₄ is P or isabsent; and as is I, G, or R; and α₆ is A, F, or G.

In some aspects, when α₃, is I, α₄ is P; as is I or R; and α₆ is F or G.In some aspects, when α₃, is L, α₄ is P; as is I; and α₆ is A or G. Insome aspects, when α₄, is P, α₃ is I or L; as is I or R; and α₆ is A, F,or G. In some aspects, when as, is I, α₃ is I or L; α₄ is P; and α₆ isA, F, or G. In some aspects, when α₆, is F, α₃ is I or is absent; α₄ isP or is absent; and as is I or G. In some aspects, when α₆, is G, α₃ isI or L; α₄ is P; and as is I or R.

In some aspects, when α₃ is L, α₄ is P; as is I; and α₆ is A. In someaspects, when α₃ is I, α₄ is P; as is I; and α₆ is F. In some aspects,when α₃ is absent, α₄ is absent; as is G; and α₆ is F. In some aspects,when α₃ is L, α₄ is P; as is I; and α₆ is G. In some aspects, when α₃ isI, α₄ is P; as is R; and α₆ is G.

In some embodiments, the antibody comprises a Kabat CDR-H2 sequencedefined by the consensus sequence β₁-I-I-P-β₅-β₆-G-β₈-A-N-Y-A-Q-K-F-G-Q(SEQ ID NOS: 74 and 76-79) where β₁ is S or G; β₅ is I, E, S, or T; β₆is F, I, or S; and β₈ is I or T.

In some aspects, when β₁ is S, β₅ is E, I, or S; β₆ is I or F; and β₈ isI or T. In some aspects, when β₁ is G, β₅ is I or T; β₆ is F or S; andβ₈ is T. In some aspects, when β₅ is I, Pi is G or S; β₆ is F or S; andβ₈ is T. In some aspects, when β₆ is F, β₁ is G or S; β₅ is E, I, or T;and β₈ is I or T. In some aspects, when β₈ is T, Pi is G or S; β₅ is I,S, or T; and β₆ is F, I, or S.

In some aspects, when β₁ is S, β₅ is I; β₅ is F; and β₈ is T. In someaspects, when β₁ is S, β₅ is E; β₅ is F; and β₈ is I. In some aspects,when β₁ is S, β₅ is S; β₅ is I; and β₈ is T. In some aspects, when β₁ isG, β₅ is I; β₅ is F; and β₈ is T. In some aspects, when β₁ is G, β₅ isI; β₅ is S; and β₈ is T. In some aspects, when β₁ is G, β₅ is T; β₅ isF; and β₈ is T.

2.8.5. Kabat CDR-H1 Consensus Sequences

In some embodiments, the antibody comprises a Kabat CDR-H1 sequencedefined by the consensus sequence S-Y-Δ₃-M-Δ₅ (SEQ ID NOS: 25-29 and44-45), where Δ₃ is E, F, Q, or Y and Δ₅ is H or Y.

In some aspects, when Δ₃ is Y, Δ₅ is H or Y. In some aspects, when Δ₅ isH, Δ₃ is E, F, Q, or Y.

In some aspects, Δ₃ is Y when Δ₅ is H. In some aspects, Δ₃ is Y when Δ₅is Y. In some aspects, Δ₃ is E when Δ₅ is H. In some aspects, Δ₃ is Qwhen Δ₅ is H. In some aspects, Δ₃ is F when Δ₅ is H.

In some embodiments, the antibody comprises a Kabat CDR-H1 sequencedefined by the consensus sequence θ₁-θ₂-θ₃-I-S(SEQ ID NOS: 30-37), whereOi is A, H, K, L, S, or W; θ₂ is L, M, N, or T; and θ₃ is A or P.

In some aspects, when θ₁ is S, θ₂ is L or N and θ₃ is A or P. In someaspects, when θ₂ is L, θ₁ is K, L, S, or W and θ₃ is A or P. In someaspects, when θ₃ is A, θ₁ is A, H, K, L, S, or W and θ₂ is L, M, N, orT.

In some aspects, θ₁ is S, when θ₂ is L and θ₃ is A. In some aspects, θ₁is K, when θ₂ is L and θ₃ is A. In some aspects, θ₁ is H when θ₂ is Tand θ₃ is A. In some aspects, θ₁ is S when θ₂ is L and θ₃ is P. In someaspects, θ₁ is L when θ₂ is L and θ₃ is A. In some aspects, θ₁ is S whenθ₂ is N and θ₃ is A. In some aspects, θ₁ is A when θ₂ is M and θ₃ is A.In some aspects, θ₁ is W when θ₂ is L and θ₃ is A.

In some embodiments, the antibody comprises a Kabat CDR-H1 sequencedefined by the consensus sequence η₁-Y-η₃-I-S SEQ ID NOS: 38-41), whereη₁ is S, K, N, or R and η₃ is A or G.

In some aspects, η₁ is S where η₃ is A or G. In some aspects, η₃ is Awhere η₁ is N or S. In some aspects, η₃ is G where η₁ is K, R, or S.

In some aspects, when η₁ is S, η₃ is A. In some aspects, when η₁ is S,η₃ is G. In some aspects, when η₁ is K, η₃ is G. In some aspects, whenη₁ is R, η₃ is G. In some aspects, when η₁ is N, η₃ is A.

2.8.6. CDR-L3 Consensus Sequences

In some embodiments, the antibody comprises a CDR-L3 sequence defined bythe consensus sequence Q-Q-Y-π₄-π₅-π₆-π₇-T (SEQ ID NOS: 141-147), whereπ₄ is G, H, or Y; π₅ is S, N, F, G, or R; π₆ is S, Y, A, G, or R; and π₇is P, I, or L.

In some aspects, π₄ is H when π₅ is S, N, G, or R; π₆ is Y, A, G, or R;and π₇ is I or L. In some aspects, π₅ is S, when π₄ is G or H; π₆ is S,Y, or A; and π₇ is P, I or L. In some aspects, π₆ is Y, when π₄ is H orY; π₅ is S or F; and π₇ is I. In some aspects, π₆ is A when π₄ is H; π₅is N or S; and π₇ is I or L. In some aspects, π₇ is I when π₄ is H or Y;π₅ is S, N, F, G, or R; and π₆ is Y, A, G, or R.

In some aspects, π₄ is G when π₅ is S; π₆ is S; and π₇ is P. In someaspects, π₄ is H when π₅ is S; π₆ is Y; and π₇ is I. In some aspects, π₄is H when π₅ is N; π₆ is I; and π₇ is A. In some aspects, π₄ is Y whenπ₅ is F; π₆ is Y; and π₇ is I. In some aspects, π₄ is H when π₅ is S; π₆is A; and π₇ is L. In some aspects, π₄ is H when π₅ is G; π₆ is G; andπ₇ is I. In some aspects, π₄ is H when π₅ is R; π₆ is R; and π₇ is I.

In some embodiments, the antibody comprises a CDR-L3 sequence defined byconsensus sequence Q-Q-λ₃-λ₄-λ₅-λ₆-P-T (SEQ ID NOS: 148-150), where λ₃is R, F, H, S, L, D, Y, or V; λ₄ is S, V, T, G, L, Y, or N; λ₅ is N, L,F, K, or V; and λ₆ is W, F, Y, or L.

In some aspects, λ₃ is R, when λ₄ is S or N; λ₅ is N or F; and λ₄ is Wor Y. In some aspects, λ₃ is H when λ₄ is V or T; λ₅ is N or V; and λ₆is F or W. In some aspects, λ₃ is S when λ₄ is V or Y; λ₅ is F; and λ₆is W or L. In some aspects, λ₄ is V when λ₃ is F, H, S, or D; λ₅ is L,N, or F; and λ₆ is W or F. In some aspects, λ₄ is T when λ₃ is L or H;λ₅ is K or V; and λ₆ is W. In some aspects, λ₅ is N when λ₃ is R, H, orV; λ₄ is S, V, or L; and λ₆ is W, F, or Y. In some aspects, λ₅ is L whenλ₃ is F, D, or Y; λ₄ is V or G; and λ₂ is W or F. In some aspects, λ₅ isF when λ₃ is S or R; λ₄ is V, Y, or N; and λ₆ is W, L, or Y. In someaspects, λ₆ is W when λ₃ is R, F, S, L, D, or H; λ₄ is S, V, or T; andλ₅ is N, L, F, K, or V. In some aspects, λ₄ is F when λ₃ is H or Y; λ₄is V or G; and λ₅ is N or L. In some aspects, λ₆ is Y when λ₃ is V or R;λ₄ is L or N; and λ₅ is N or F.

In some aspects, λ₃ is R when λ₄ is S; λ₅ is N; and λ₆ is W. In someaspects, λ₃ is F when λ₄ is V; λ₅ is L; and 4 is W. In some aspects, λ₃is H when λ₄ is V; λ₅ is N; and λ₆ is F. In some aspects, λ₃ is S whenλ₄ is V; λ₅ is F; and λ₄ is W. In some aspects, λ₃ is L when λ₁ is T; λ₅is K; and λ₆ is W. In some aspects, λ₃ is D when λ₄ is V; λ₅ is L; andλ₆ is W. In some aspects, λ₃ is Y when λ₄ is G; λ₅ is L; and λ₆ is F. Insome aspects, λ₃ is H when λ₄ is T; λ₅ is V; and λ₆ is W. In someaspects, λ₃ is V when λ₄ is L; λ₅ is N; and λ₆ is Y. In some aspects, λ₃is S when λ₄ is Y; λ₅ is F; and λ₆ is L. In some aspects, λ₃ is R whenλ₄ is N; λ₅ is F; and 4 is Y.

In some embodiments, the antibody comprises a CDR-L3 sequence defined bythe consensus sequence Q-Q-Y-ρ₃-ρ₄-W-P-L-T (SEQ ID NOS: 151 and 152),where ρ₃ is N or L and ρ₄ is N or L.

In some aspects, ρ₃ is N when ρ₄ is L. In some aspects, ρ₃ is L when ρ₄is L.

In some embodiments, the antibody comprises a CDR-L3 sequence defined bythe consensus sequence Q-Q-ω₃-ω₄-ω₅-ω₆-P-ω₅-T (SEQ ID NOS: 153-156),where ω₃ is Y or F; ω₄ is Y or W; ω₅ is S, L, T, or F; ω₆ is T, Y, or F;and ω₅ is L or P.

In some aspects, ω₃ is Y when ω₄ is Y or W; ω₅ is S, L, or T; ω₆ is T orY; and ω₅ is L. In some aspects, ω₄ is Y when ω₃ is Y or F; ω₅ is S, L,or F; ω₆ is T or Y; and ω₅ is L or P. In some aspects, ω₆ is Y when ω₃is Y; ω₄ is Y or W; ω₅ is L or T; and ω₅ is L. In some aspects, ω₅ is Lwhen ω₃ is Y; ω₄ is Y or W; ω₅ is S, L, or T; and ω₆ is T or Y.

In some aspects, ω₃ is Y when ω₄ is Y; ω₅ is S; ω₆ is T; and ω₅ is L. Insome aspects, ω₃ is Y when ω₄ is Y; ω₅ is L; ω₆ is Y; and ω₈ is L. Insome aspects, ω₃ is Y when ω₄ is W; ω₅ is T; ω₆ is Y; and ω₅ is L. Insome aspects, ω₃ is F when ω₄ is Y; ω₅ is F; ω₆ is F; and ω₅ is P.

2.8.7. CDR-L2 Consensus Sequences

In some embodiments, the antibody comprises a CDR-L2 sequence defined bythe consensus sequence ψ₁-A-S-ψ₄-R-ψ₆-ψ₇ (SEQ ID NOS: 125-136), where ψ₁is G or Y, is S or N; ψ₆ is A or H; and ψ₇ is T, Y, or N.

In some aspects, ψ₁ is G when ψ₄ is S or N; ψ₆ is A or H; and ψ₇ is T orN. In some aspects, ψ₁ is Y when is S or N; ψ₆ is A; and ψ₇ is Y or T.In some aspects, ψ₄ is S when ψ₁ is G or Y; ψ₆ is A; and ψ₇ is T, Y, orN. In some aspects, ψ₄ is N when ψ₁ is G or Y; ψ₆ is H or A; and ψ₇ isT. In some aspects, ψ₆ is A when ψ₁ is G or Y; ψ₄ is S or N; and ψ₇ isT, Y, or N. In some aspects, ψ₇ is T when ψ₁ is G or Y; ψ₄ is S or N;and ψ₆ is A or H.

In some aspects, ψ₁ is G when ψ₄ is S; ψ₆ is A; and ψ₇ is T. In someaspects, ψ₁ is G when ψ₄ is N; ψ₆ is H; and ψ₇ is T. In some aspects, ψ₁is Y when ψ₄ is S; ψ₆ is A; and ψ₇ is Y. In some aspects, ψ₁ is G whenψ₄ is S; ψ₆ is A; and ψ₇ is N. In some aspects, ψ₁ is Y when ψ₄ is N; ψ₆is A; and ψ₇ is T.

In some embodiments, the antibody comprises a CDR-L2 sequence defined bythe consensus sequence D-A-S-χ₄-R-A-T (SEQ ID NOS: 138 and 139), where£₄ is N or K.

In some aspects, χ₄ is N. In some aspects, χ₄ is K.

In some embodiments, the antibody comprises a CDR-L2 sequence defined bythe consensus sequence W-A-S-T-R-σ₆-S(SEQ ID NOS: 131 and 133-134),where σ₆ is A, E, or Q.

In some aspects, σ₆ is A. In some aspects, σ₆ is E. In some aspects, σ₆is Q.

2.8.8. CDR-L1 Consensus Sequences

In some embodiments, the antibody comprises a CDR-L1 sequence defined bythe consensus sequence ϕ₁-A-S-ϕ₄-ϕ₅-V-ϕ₇-ϕ₈-ϕ₉-Y-L-A (SEQ ID NOS:1101-114), where ϕ₁ is E, K, or R; ϕ₄ is Q or E; ϕ₅ is S or Y; ϕ₇ is Sor A; ϕ₈ is S or Y; and ϕ₉ is D or S.

In some aspects, ϕ₁ is R when ϕ₄ is Q or E; ϕ₅ is S or Y; ϕ₇ is S or A;ϕ₈ is S or Y; and ϕ₉ is S or D. In some aspects, ϕ₄ is E when ϕ₁ is K orR; ϕ₅ is S; ϕ₇ is S; ϕ₈ is S; and ϕ₉ is S. In some aspects, ϕ₄ is Q whenϕ₁ is E or R; ϕ₅ is S or Y; ϕ₇ is S or A; ϕ₈ is S or Y; and ϕ₉ is S orD. In some aspects, ϕ₅ is S when ϕ₁ is E, K, or R; ϕ₄ is E or Q; ϕ₇ is Sor A; ϕ₈ is S or Y; and ϕ₉ is S or D. In some aspects, ϕ₇ is S when ϕ₁is E, K, or R; ϕ₄ is E or Q; ϕ₅ is S or Y; ϕ₈ is S or Y; and ϕ₉ is S orD. In some aspects, ϕ₈ is S when ϕ₁ is K or R; ϕ₄ is E or Q; ϕ₅ is S or5; ϕ₇ is A or S; and ϕ₉ is S or D. In some aspects, ϕ₈ is R when ϕ₁ is Eor R; ϕ₄ is Q; ϕ₅ is S; ϕ₇ is S; and ϕ₉ is S. In some aspects, ϕ₉ is Swhen ϕ₁ is E, K, or R; ϕ₄ is E or Q; ϕ₅ is S or Y; ϕ₇ is A or S; and ϕ₈is S or Y.

In some aspects, ϕ₁ is K when ϕ₄ is E; ϕ₅ is S; ϕ₇ is S; ϕ₈ is S; and ϕ₉is S. In some aspects, ϕ₁ is E, when ϕ₄ is Q; ϕ₅ is S; ϕ₇ is S; ϕ₈ is Y;and ϕ₉ is S. In some aspects, ϕ₁ is R when ϕ₄ is Q; ϕ₅ is S; ϕ₇ is S; ϕ₈is S; and ϕ₉ is D. In some aspects, ϕ₁ is R when ϕ₄ is Q; ϕ₅ is S; ϕ₇ isS; ϕ₈ is S; and ϕ₉ is S. In some aspects, ϕ₁ is R when ϕ₄ is Q; ϕ₅ is S;ϕ₇ is A; ϕ₈ is S; and ϕ₉ is S. In some aspects, ϕ₁ is R when ϕ₄ is Q; ϕ₅is S; ϕ₇ is S; ϕ₈ is Y; and ϕ₉ is S. In some aspects, ϕ₁ is R when ϕ₄ isE; ϕ₅ is S; ϕ₇ is S; ϕ₈ is S; and ϕ₉ is S. In some aspects, ϕ₁ is R whenϕ₄ is Q; ϕ₅ is Y; ϕ₇ is S; ϕ₈ is S; and ϕ₉ is S.

In some embodiments, the antibody comprises a CDR-L1 sequence defined bythe consensus sequence ∂₁-A-S-Q-∂₅-∂₆-∂₇-∂₈-∂₉-L-∂₁₁ (SEQ ID NOS: 118and 120-123), where ∂₁ is Q or R1; ∂₅ is D or S; ∂₆ is I or V; ∂₇ is Gor S; ∂₈ is N, R, or S; ∂₉ is N, Y, or W; and ∂₁₁ is A or N.

In some aspects, when ∂₁ is R, ∂₅ is S; ∂₆ is I or V; ∂₇ is G or S; ∂₈is R or S; ∂₉ is N, Y, or W; and ∂₁₁ is A. In some aspects, when ∂₅ isS, ∂₁ is R; ∂₆ is I or V; ∂₇ is G or S; ∂₈ is R or S; ∂₉ is N, Y, or W;and ∂₁₁ is A. In some aspects, when ∂₆ is I, ∂₁ is Q or R; ∂₅ is D or S;∂₇ is S; ∂₈ is N or S; ∂₉ is Y or W; and ∂₁₁ is A or N. In some aspects,when ∂₆ is V, ∂₁ is R; ∂₅ is S; ∂₇ is G or S; ∂₈ is R or S; ∂₉ is N orW; and ∂₁₁ is A. In some aspects, when ∂₇ is S, ∂₁ is Q or R; ∂₅ is D orS; ∂₆ is I or V; ∂₈ is N, S, or R; ∂₉ is Y or W; and ∂₁₁ is A or N. Insome aspects, when ∂₈ is S, ∂₁ is R; ∂₅ is S; ∂₆ is I or V; ∂₇ is S; ∂₉is N, Y, or W; and ∂₁₁ is A. In some aspects, when ∂₉ is Y, ∂₁ is Q orR; ∂₅ is D or S; ∂₆ is I or V; ∂₇ is S; ∂₈ is N, S, or R; and ∂₁₁ is Aor N. In some aspects, when ∂₁₁ is A, ∂₁ is R; ∂₅ is S; ∂₆ is I or V; ∂₇is S or G; ∂₈ is S, or R; and ∂₉ is N, W, or Y.

In some aspects, when ∂₁ is R, ∂₅ is S; ∂₆ is V; ∂₇ is S; ∂₈ is S; ∂₉ isY; and ∂₁₁ is A. In some aspects, when ∂₁ is Q, ∂₅ is D; ∂₆ is I; ∂₇ isS; ∂₈ is N; ∂₉ is Y; and ∂₁₁ is N. In some aspects, when ∂₁ is R, ∂₅ isS; ∂₆ is V; ∂₇ is S; ∂₈ is R; ∂₉ is Y; and ∂₁₁ is A. In some aspects,when ∂₁ is R, ∂₅ is S; ∂₆ is V; ∂₇ is G; ∂₈ is S; ∂₉ is N; and ∂₁₁ is A.In some aspects, when ∂₁ is R, ∂₅ is S; ∂₆ is I; ∂₇ is S; ∂₈ is S; ∂₉ isW; and ∂₁₁ is A.

In some embodiments, the antibody comprises a CDR-L1 sequence defined bythe consensus sequence K-S-S-Γ₄-S-V-L-Γ₈-S-Γ₁₀-N-N-K-N-Y-L-A (SEQ IDNOS: 115-117), where Γ₄ is Q, R or K; Γ₈ is F or Y; and Γ₁₀ is S or N.

In some aspects, Γ₄ is Q when Γ₈ is F or Y and Γ₁₀ is S. In someaspects, Γ₈ is F when Γ₄ is Q or R and Γ₁₀ is S. In some aspects, Γ₈ isY when Γ₄ is K or Q and Γ₁₀ is S or N. In some aspects, Γ₁₀ is S when Γ₄is R or Q and Γ₈ is F or Y.

In some aspects, Γ₄ is Q when Γ₈ is Y and Γ₁₀ is S. In some aspects, Γ₄is K when Γ₈ is Y and Γ₁₀ is N. In some aspects, Γ₄ is Q when Γ₈ is Fand Γ₁₀ is S. In some aspects, Γ₄ is R when Γ₈ is F and Γ₁₀ is S.

3. Germline

In some embodiments, the antibody that specifically binds CD39 is anantibody comprising a variable region that is encoded by a particulargermline gene, or a variant thereof. The illustrative antibodiesprovided herein comprise variable regions that are encoded by the heavychain variable region germline genes VH1-46, VH1-69, 1-69, and VH1-46,or variants thereof and the light chain variable region germline genesVK3-20, VK3-11, VK4-01, VK3, and VK3-15, or variants thereof. One ofskill in the art would recognize that the CDR sequences provided hereinmay also be useful when combined with variable regions encoded by othervariable region germline genes, or variants thereof. In particular, theCDR sequences provided herein may be useful when combined with variableregions encoded by variable region germline genes, or variants thereof,that are structurally similar to the variable region germline genesrecited above. For example, in some embodiments, a CDR-H sequenceprovided herein may be combined with a variable region encoded by avariable region germline gene selected from the VH1 or VH3 family, or avariant thereof. In some embodiments, a CDR-L sequence provided hereinmay be combined with a variable region encoded by a variable regiongermline gene selected from the Vλ3, Vκ1, Vκ3, and VK4 families, or avariant thereof

4. Affinity

In some embodiments, the affinity of the antibody for CD39, as indicatedby K_(D), is less than about 10⁻⁵ M, less than about 10⁻⁶ M, less thanabout 10⁻⁷ M, less than about 10⁻⁸ M, less than about 10⁻⁹ M, less thanabout 10⁻¹⁰ M, less than about 10⁻¹¹ M, or less than about 10⁻¹²M. Insome embodiments, the affinity of the antibody is between about 10⁻⁷Mand 10⁻¹¹M. In some embodiments, the affinity of the antibody is betweenabout 10⁻⁷ M and 10⁻¹⁰ M. In some embodiments, the affinity of theantibody is between about 10⁻⁷M and 10⁻⁹ M. In some embodiments, theaffinity of the antibody is between about 10⁻⁷ M and 10⁻⁸ M. In someembodiments, the affinity of the antibody is between about 10⁻⁸ M and10⁻¹¹ M. In some embodiments, the affinity of the antibody is betweenabout 10⁻⁸ M and 10⁻¹⁰ M. In some embodiments, the affinity of theantibody is between about 10⁻⁹ M and 10⁻¹¹ M. In some embodiments, theaffinity of the antibody is between about 10⁻¹⁰ M and 10⁻¹¹M.

In some embodiments, the affinity of the antibody for human CD39 isbetween about 4.09×10⁻⁷ M and 7.31×10⁻¹¹ M. In some embodiment, theaffinity of the antibody for human CD39 is about 1.14×10⁻⁷ M, about1.31×10⁻⁷ M, about 1.67×10⁻⁷ M, about 1.43×10⁻⁷ M, about 1.30×10⁻⁸ M,about 1.27×10⁻⁷ M, about 1.13×10⁻⁷ M, about 1.60×10⁻⁷ M, about 1.34×10⁻⁹M, about 1.16×10⁻⁹ M, about 7.31×10⁻¹¹ M, about 7.60×10⁻¹⁰ M, about2.66×10⁻¹⁰ M, about 9.22×10⁻¹⁰ M, about 6.72×10⁻¹⁰ M, about 9.24×10⁻¹⁰M, about 5.58×10⁻¹⁰ M, about 5.48×10⁻⁷ M, about 3.37×10⁻⁷ M, about3.11×10⁻⁷ M, about 1.88×10⁻⁷ M, about 1.63×10⁻⁷ M about 1.64×10⁻⁷ M,about 1.01×10⁻⁷ M, about 2.44×10⁻⁷ M, about 4.09×10⁻⁷ M, about 3.35×10⁻⁸M, about 1.91×10⁻⁸M, about 1.73×10⁻⁷ M, or about 2.39×10⁻⁷ M.

In some embodiments the antibody has a k_(on) when associating withhuman CD39 of between about 1.93×10⁴ M⁻¹×sec⁻¹ and about 1.72×10⁶M⁻¹×sec⁻¹. In some embodiments the antibody has a k_(a) when associatingwith human CD39 of about 6.59×10⁴ m⁻¹×sec⁻¹, about 1.93×10⁴ M⁻¹×sec⁻¹,about 4.44×10⁵M⁻¹×sec⁻¹, about 2.72×10⁵ M⁻¹×sec⁻¹, about 6.39×10⁵M⁻¹×sec⁻¹, about 8.93×10⁵ M⁻¹×sec⁻¹, about 9.55×10⁵ M⁻¹×sec⁻¹, about2.11×10⁵ M⁻¹×sec⁻¹, about 1.17×10⁵ M⁻¹×sec⁻¹, about 2.02×10⁵ M⁻¹×sec⁻¹,about 1.76×10⁵ m⁻¹×sec⁻¹, about 1.72×10⁵ M⁻¹×sec⁻¹, about2.73×10⁵M⁻¹×sec⁻¹, about 1.43×10⁵ M⁻¹×sec⁻¹, about 9.01×10⁵ M⁻¹×sec⁻¹,about 3.13×10⁵ M⁻¹×sec⁻¹, about 5.03×10⁵ M⁻¹×sec⁻¹, about 3.02×10⁵M⁻¹×sec⁻¹, about 2.73×10⁵ M⁻¹×sec⁻¹, about 1.78×10⁵ M⁻¹×sec⁻¹, about2.98×10⁵ m⁻¹×sec⁻¹, about 4.31×10⁵ M⁻¹×sec⁻¹, about 2.27×10⁵M⁻¹×sec⁻¹,about 3.14×10⁵ M⁻¹×sec⁻¹, about 2.81×10⁵ M⁻¹×sec⁻¹, about 4.73×10⁵M⁻¹×sec⁻¹, about 3.26×10⁵ M⁻¹×sec⁻¹, about 1.73×10⁵ M⁻¹×sec⁻¹, about2.68×10⁵ M⁻¹×sec⁻¹, about 2.63×10⁵ M⁻¹×sec⁻¹, about 3.82×10⁵ m⁻¹×sec⁻¹,about 2.46×10⁵ M⁻¹×sec⁻¹, about 3.11×10⁵ M⁻¹×sec⁻¹, about 4.53×10⁵M⁻¹×sec⁻¹, about 4.63×10⁵ M⁻¹×sec⁻¹, about 9.01×10⁵ M⁻¹×sec⁻¹, about1.03×10⁶ M⁻¹×sec⁻¹, about 1.52×10⁶ M⁻¹×sec⁻¹, or about 3.53×10⁵M⁻¹×sec⁻¹.

In some embodiments the antibody has a k_(off) of about 7.51×10⁻³ sec⁻¹,about 6.33×10⁻² sec⁻¹, about 4.70×10⁻² sec⁻¹, about 7.82×10⁻⁴ sec⁻¹,about 4.70×10⁻² sec⁻¹, about 1.05×10⁻² sec⁻¹, about 3.65×10⁻¹ sec⁻¹,about 1.60×10⁻¹ sec⁻¹, about 7.11×10⁻³ sec⁻¹, about 6.44×10⁻³ sec⁻¹,about 3.85×10⁻² sec⁻¹, about 2.30×10⁻² sec⁻¹, about 5.33×10⁻² sec⁻¹,about 9.14×10⁻² sec⁻¹, about 1.80×10⁻³ sec⁻¹, about 8.15×10⁻³ sec⁻¹,about 3.85×10⁻⁴ sec⁻¹, about 1.34×10⁻⁴ sec⁻¹, about 2.29×10⁻⁴ sec⁻¹,about 4.37×10⁻³ sec⁻¹, about 3.71×10⁻³ sec⁻¹, about 4.06×10⁻³ sec⁻¹,about 6.66×10⁻² sec⁻¹, about 2.02×10⁻³ sec⁻¹, about 2.00×10⁴ sec⁻¹,about 5.26×10⁻³ sec⁻¹, about 1.13×10⁻² sec⁻¹, about 3.28×10⁻³ sec⁻¹,about 2.76×10⁻³ sec⁻¹, about 2.86×10⁻⁴ sec⁻¹, about 2.43×10⁻⁴ sec⁻¹,about 2.13×10⁻⁴ sec⁻¹, about 6.09×10⁻⁴ sec⁻¹, about 8.39×10⁴ sec⁻¹,about 8.15×10⁻³ sec⁻¹, about 1.32×10⁻⁴ sec⁻¹, about 1.11×10⁴ sec⁻¹,about 2.43×10⁻⁴ sec⁻¹, about 2.13×10⁻⁴ sec⁻¹, about 6.09×10⁻⁴ sec⁻¹,about 8.15×10⁻³ sec⁻¹, about 1.32×10⁴ sec⁻¹, or about 1.11×10⁴ sec⁻¹.

In some aspects, the K_(D), k_(a), and k_(d) are determined at 25° C. Insome embodiments, the K_(D), k_(a), and k_(d) are determined by surfaceplasmon resonance. In some embodiments, the K_(D), k_(a), and k_(d) aredetermined according to the methods described in the examples.

5. Inhibition of CD39

In some aspects, the antibody decreases affinity of CD39 to itssubstrate. In some aspects, the antibody inhibits CD39 function on tumorcells. In some aspects, the antibody inhibits or impedes the release ofADP or AMP from CD39. In some aspects, the antibody inhibits or impedesCD39 processivity.

In some aspects, the antibody binds CD39 but does not inhibit ATPase. Insome aspects, the antibody binds CD39 and inhibits extracellular CD39activity but not cellular ATPase activity. In some aspects, the antibodybinds both the extracellular domain of CD39 and cellular CD39 and caninhibit both the extracellular domain of CD39 and cellular CD39. In someaspects, the antibodies do not compete with A1 and/or others in bindingto the extracellular domain.

6. CD39 Assays

In some embodiments, the antibody binds to an epitope of CD39. In someaspects, CD39 has a sequence identical to the amino acid sequence setforth in SEQ ID NO: 249. In some aspects, the epitope has an amino acidsequence that is identical to the amino acid sequence set forth in SEQID NO: 249. In some aspects, the epitope is in an extracellular domainof CD39. In some aspects, the extracellular domain corresponds to all orat least a portion of amino acids 38-478 of SEQ ID NO: 249. In someaspects, the epitope has an amino acid sequence that is 60%, 65%, 70%,75%, 80%, 85%, 90%, or 95% identical to the sequence set forth in SEQ IDNO: 249 or all or a portion of the extracellular domain. In someaspects, the epitope has a sequence that is identical or corresponds toresidues 143-158 and/or residues 274-277 of SEQ ID NO: 249. In someaspects, the epitope is in the region of E143 to N158 on the human CD39polypeptide having the sequence set forth in SEQ ID NO: 249. In someaspects, the epitope has a sequence that has a 60%, 65%, 70%, 75%, 80%,85%, 90%, or 95% identity to residues 143-158 or 274-277 of the sequenceset forth in SEQ ID NO: 249. In some aspects, the epitope has 1, 2, 3,4, 5, 6, 7, 8, or 9 substitutions from residues 143-158 of the sequenceforth in SEQ ID NO: 249. In some aspects, the epitope has 1, 2 or 3substitutions from residues 274-277 of SEQ ID NO: 249. In some aspects,the antibody makes contact with any of the residues set forth in FIG.14E, Table 1. In some aspects, the antibody makes contact with any ofthe residues set forth in FIG. 14E, Table 2. In some aspects, theantibody binds to D150, E153, and/or R154 or to N99 and none, one, two,or three of D150, E153, and R154 or to any of the above alone or incombination.

In some aspects, the antibody competes with 1, 2, 3, 4, or 5 ofantibodies 27536, 27571, 28347, 27579, or 27597 as set forth in FIG.14A. In some aspects, the antibody competes with 1, 2, 3, 4, or 5antibodies 27536, 27571, 28347, 27579, or 27597 as set forth in FIG.14A. In some aspects, the antibody competes with 1, 2, or 3 ofantibodies 25571, 27536, or 27549 as set forth in FIG. 14C. In someaspects, the antibody competes with 1, 2, or 3 of antibodies 25571,27536, or 27549 set forth in FIG. 14C.

In some aspects, the antibody inhibits conversion by CD39 of ATP to ADPand/or ADP to AMP. In some aspects, the antibody inhibits plateletaggregation. In some aspects, the antibody decreases or preventsactivation of phospho antigen specific T cells selected from MATT cellsand γδ T cells. In some aspects, the antibody inhibits angiogenesis. Insome aspects, the antibody decreases levels of phosphate, ADP, AMP,and/or adenosine and/or increasing levels of ATP. In some aspects, theantibody increases T effector cell function. In some aspects, theantibody decreases the number of regulatory T cells in tissues or incirculation. In some aspects, the antibody decreases the regulatory Tcells or regulatory T cell activity. In some aspects, the antibodyincreases B cell function. In some aspects, the antibody increasesantigen presenting cell function. In some aspects, the antibody inhibitsprocessing of at least one of phospho-antigen from phosphorylatedisoprenoid, phosphorylated vitamin B metabolite, and/or phosphorylatedriboflavin.

In some aspects, the antibody has limited ability to limit ATPase of thesoluble or extracellular domain. In some aspects, the antibody haslimited ability to inhibit ATPase of the cellular and/or extracellulardomain of CD39.

7. Glycosylation Variants

In certain embodiments, an antibody may be altered to increase, decreaseor eliminate the extent to which it is glycosylated. Glycosylation ofpolypeptides is typically either “N-linked” or “O-linked.”

“N-linked” glycosylation refers to the attachment of a carbohydratemoiety to the side chain of an asparagine residue. The tripeptidesequences asparagine-X-serine and asparagine-X-threonine, where X is anyamino acid except proline, are the recognition sequences for enzymaticattachment of the carbohydrate moiety to the asparagine side chain.Thus, the presence of either of these tripeptide sequences in apolypeptide creates a potential glycosylation site.

“O-linked” glycosylation refers to the attachment of one of the sugarsN-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, mostcommonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

Addition or deletion of N-linked glycosylation sites to the antibody maybe accomplished by altering the amino acid sequence such that one ormore of the above-described tripeptide sequences is created or removed.Addition or deletion of O-linked glycosylation sites may be accomplishedby addition, deletion, or substitution of one or more serine orthreonine residues in or to (as the case may be) the sequence of anantibody.

In certain embodiments, the antibody is glycosylated. In certainembodiments, the antibody is deglycosylated. Carbohydrates may beremoved by standard techniques. In certain embodiments, the antibody isaglycosylated, for instance by expression in a system that does notglycosylate.

8. Fc Variants

In certain embodiments, amino acid modifications may be introduced intothe Fc region of an antibody provided herein to generate an Fc regionvariant. In certain embodiments, the Fc region variant possesses some,but not all, effector functions. Such antibodies may be useful, forexample, in applications in which the half-life of the antibody in vivois important, yet certain effector functions are unnecessary ordeleterious. Examples of effector functions include complement-dependentcytotoxicity (CDC) and antibody-directed complement-mediatedcytotoxicity (ADCC). Numerous substitutions or substitutions ordeletions with altered effector function are known in the art.

An alteration in in CDC and/or ADCC activity can be confirmed using invitro and/or in vivo assays. For example, Fc receptor (FcR) bindingassays can be conducted to measure FcγR binding. The primary cells formediating ADCC, NK cells, express FcγRIII only, whereas monocytesexpress FcγR1, FcγRII and FcγRIII. FcR expression on hematopoietic cellsis summarized in Ravetch and Kinet, Ann. Rev. Immunol., 1991, 9:457-492.

Non-limiting examples of in vitro assays to assess ADCC activity of amolecule of interest are provided in U.S. Pat. Nos. 5,500,362 and5,821,337; Hellstrom et al., Proc. Natl. Acad. Sci. USA., 1986,83:7059-7063; Hellstrom et al., Proc. Natl. Acad. Sci. USA., 1985,82:1499-1502; and Bruggemann et al., J. Exp. Med., 1987, 166:1351-1361.Useful effector cells for such assays include peripheral bloodmononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively,or additionally, ADCC activity of the molecule of interest may beassessed in vivo, using an animal model such as that disclosed in Clyneset al. Proc. Natl. Acad. Sci. USA., 1998, 95:652-656.

C1q binding assays may also be carried out to confirm that the antibodyis unable to bind C1q and hence lacks CDC activity. Examples of C1qbinding assays include those described in WO 2006/029879 and WO2005/100402.

Complement activation assays include those described, for example, inGazzano-Santoro et al., J. Immunol. Methods, 1996, 202:163-171; Cragg etal., Blood, 2003, 101:1045-1052; and Cragg and Glennie, Blood, 2004,103:2738-2743.

FcRn binding and in vivo clearance (half-life determination) can also bemeasured, for example, using the methods described in Petkova et al.,Intl. Immunol., 2006, 18:1759-1769.

9. Preparation of Antibodies 9.1. Antigen Preparation

The CD39 antigen to be used for production of antibodies may be intactCD39 or a fragment of CD39. The intact CD39, or fragment of CD39, may bein the form of an isolated protein or expressed by a cell. Other formsof CD39 useful for generating antibodies will be apparent to thoseskilled in the art.

9.2. Monoclonal Antibodies

Monoclonal antibodies may be obtained, for example, using the hybridomamethod first described by Kohler et al., Nature, 1975, 256:495-497,and/or by recombinant DNA methods (see e.g., U.S. Pat. No. 4,816,567).Monoclonal antibodies may also be obtained, for example, using phage oryeast-based libraries. See e.g., U.S. Pat. Nos. 8,258,082 and 8,691,730.

In the hybridoma method, a mouse or other appropriate host animal isimmunized to elicit lymphocytes that produce or are capable of producingantibodies that will specifically bind to the protein used forimmunization. Alternatively, lymphocytes may be immunized in vitro.Lymphocytes are then fused with myeloma cells using a suitable fusingagent, such as polyethylene glycol, to form a hybridoma cell. See GodingJ. W., Monoclonal Antibodies: Principles and Practice 3^(rd) ed. (1986)Academic Press, San Diego, Calif.

The hybridoma cells are seeded and grown in a suitable culture mediumthat contains one or more substances that inhibit the growth or survivalof the unfused, parental myeloma cells. For example, if the parentalmyeloma cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomastypically will include hypoxanthine, aminopterin, and thymidine (HATmedium), which substances prevent the growth of HGPRT-deficient cells.

Useful myeloma cells are those that fuse efficiently, support stablehigh-level production of antibody by the selected antibody-producingcells, and are sensitive media conditions, such as the presence orabsence of HAT medium. Among these, preferred myeloma cell lines aremurine myeloma lines, such as those derived from MOP-21 and MC-11 mousetumors (available from the Salk Institute Cell Distribution Center, SanDiego, Calif.), and SP-2 or X63-Ag8-653 cells (available from theAmerican Type Culture Collection, Rockville, Md.). Human myeloma andmouse-human heteromyeloma cell lines also have been described for theproduction of human monoclonal antibodies. See e.g., Kozbor, J.Immunol., 1984, 133:3001.

After the identification of hybridoma cells that produce antibodies ofthe desired specificity, affinity, and/or biological activity, selectedclones may be subcloned by limiting dilution procedures and grown bystandard methods. See Goding, supra. Suitable culture media for thispurpose include, for example, D-MEM or RPMI-1640 medium. In addition,the hybridoma cells may be grown in vivo as ascites tumors in an animal.

DNA encoding the monoclonal antibodies may be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of the monoclonal antibodies). Thus, thehybridoma cells can serve as a useful source of DNA encoding antibodieswith the desired properties. Once isolated, the DNA may be placed intoexpression vectors, which are then transfected into host cells such asbacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COScells, Chinese hamster ovary (CHO) cells, or myeloma cells that do nototherwise produce antibody, to produce the monoclonal antibodies.

9.3. Humanized Antibodies

Humanized antibodies may be generated by replacing most, or all, of thestructural portions of a monoclonal antibody with corresponding humanantibody sequences. Consequently, a hybrid molecule is generated inwhich only the antigen-specific variable, or CDR, is composed ofnon-human sequence. Methods to obtain humanized antibodies include thosedescribed in, for example, Winter and Milstein, Nature, 1991,349:293-299; Rader et al., Proc. Nat. Acad. Sci. USA., 1998,95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078;Queen et al., Proc. Natl. Acad. Sci. USA., 1989, 86:10029-10033; andU.S. Pat. Nos. 5,585,089, 5,693,761, 5,693,762, and 6,180,370.

9.4. Human Antibodies

Human antibodies can be generated by a variety of techniques known inthe art, for example by using transgenic animals (e.g., humanized mice).See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA., 1993,90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann etal., Year in Immuno., 1993, 7:33; and U.S. Pat. Nos. 5,591,669,5,589,369 and 5,545,807. Human antibodies can also be derived fromphage-display libraries (see e.g., Hoogenboom et al., J. Mol. Biol.,1991, 227:381-388; Marks et al., J. Mol. Biol., 1991, 222:581-597; andU.S. Pat. Nos. 5,565,332 and 5,573,905). Human antibodies may also begenerated by in vitro activated B cells (see e.g., U.S. Pat. Nos.5,567,610 and 5,229,275). Human antibodies may also be derived fromyeast-based libraries (see e.g., U.S. Pat. No. 8,691,730).

10. Vectors, Host Cells, and Recombinant Methods

The invention also provides isolated nucleic acids encoding anti-CD39antibodies, vectors and host cells comprising the nucleic acids, andrecombinant techniques for the production of the antibodies.

For recombinant production of the antibody, the nucleic acid encoding itmay be isolated and inserted into a replicable vector for furthercloning (i.e., amplification of the DNA) or expression. In some aspects,the nucleic acid may be produced by homologous recombination, forexample as described in U.S. Pat. No. 5,204,244.

Many different vectors are known in the art. The vector componentsgenerally include, but are not limited to, one or more of the following:a signal sequence, an origin of replication, one or more marker genes,an enhancer element, a promoter, and a transcription terminationsequence, for example as described in U.S. Pat. No. 5,534,615.

Illustrative examples of suitable host cells are provided below. thesehost cells are not meant to be limiting.

Suitable host cells include any prokaryotic (e.g., bacterial), lowereukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells.Suitable prokaryotes include eubacteria, such as Gram-negative orGram-positive organisms, for example, Enterobacteriaceae such asEscherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus,Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli(B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), andStreptomyces. One useful E. coli cloning host is E. coli 294, althoughother strains such as E. coli B, E. coli X1776, and E. coli W3110 aresuitable.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are also suitable cloning or expression hosts foranti-CD39 antibody-encoding vectors. Saccharomyces cerevisiae, or commonbaker's yeast, is a commonly used lower eukaryotic host microorganism.However, a number of other genera, species, and strains are availableand useful, such as Schizosaccharomyces pombe, Kluyveromyces (K. lactis,K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. drosophilarum,K. thermotolerans, and K. marxianus), Yarrowia, Pichia pastoris, Candida(C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S.occidentalis), and filamentous fungi such as, for example Penicillium,Tolypocladium, and Aspergillus (A. nidulans and A. niger).

Useful mammalian host cells include COS-7 cells, HEK293 cells; babyhamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse sertolicells; African green monkey kidney cells (VERO-76), and the like.

The host cells used to produce the anti-CD39 antibody of this inventionmay be cultured in a variety of media. Commercially available media suchas, for example, Ham's F10, Minimal Essential Medium (MEM), RPMI-1640,and Dulbecco's Modified Eagle's Medium (DMEM) are suitable for culturingthe host cells. In addition, any of the media described in Ham et al.,Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255;and U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, and5,122,469, or WO 90/03430 and WO 87/00195 may be used.

Any of these media may be supplemented as necessary with hormones and/orother growth factors (such as insulin, transferrin, or epidermal growthfactor), salts (such as sodium chloride, calcium, magnesium, andphosphate), buffers (such as HEPES), nucleotides (such as adenosine andthymidine), antibiotics, trace elements (defined as inorganic compoundsusually present at final concentrations in the micromolar range), andglucose or an equivalent energy source. Any other necessary supplementsmay also be included at appropriate concentrations that would be knownto those skilled in the art.

The culture conditions, such as temperature, pH, and the like, are thosepreviously used with the host cell selected for expression, and will beapparent to the ordinarily skilled artisan.

When using recombinant techniques, the antibody can be producedintracellularly, in the periplasmic space, or directly secreted into themedium. If the antibody is produced intracellularly, as a first step,the particulate debris, either host cells or lysed fragments, isremoved, for example, by centrifugation or ultrafiltration. For example,Carter et al. (Bio/Technology, 1992, 10:163-167) describes a procedurefor isolating antibodies which are secreted to the periplasmic space ofE. coli. Briefly, cell paste is thawed in the presence of sodium acetate(pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30minutes. Cell debris can be removed by centrifugation.

In some embodiments, the antibody is produced in a cell-free system. Insome aspects, the cell-free system is an in vitro transcription andtranslation system as described in Yin et al., mAbs, 2012, 4:217-225,incorporated by reference in its entirety. In some aspects, thecell-free system utilizes a cell-free extract from a eukaryotic cell orfrom a prokaryotic cell. In some aspects, the prokaryotic cell is Ecoli. Cell-free expression of the antibody may be useful, for example,where the antibody accumulates in a cell as an insoluble aggregate, orwhere yields from periplasmic expression are low.

Where the antibody is secreted into the medium, supernatants from suchexpression systems are generally first concentrated using a commerciallyavailable protein concentration filter, for example, an Amicon® orMillipore® Pellcon® ultrafiltration unit. A protease inhibitor such asPMSF may be included in any of the foregoing steps to inhibitproteolysis and antibiotics may be included to prevent the growth ofadventitious contaminants.

The antibody composition prepared from the cells can be purified using,for example, hydroxylapatite chromatography, gel electrophoresis,dialysis, and affinity chromatography, with affinity chromatographybeing a particularly useful purification technique. The suitability ofprotein A as an affinity ligand depends on the species and isotype ofany immunoglobulin Fc domain that is present in the antibody. Protein Acan be used to purify antibodies that are based on human γ1, γ2, or γ4heavy chains (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13).Protein G is useful for all mouse isotypes and for human γ3 (Guss etal., EMBO J., 1986, 5:1567-1575).

The matrix to which the affinity ligand is attached is most oftenagarose, but other matrices are available. Mechanically stable matricessuch as controlled pore glass or poly(styrenedivinyl)benzene allow forfaster flow rates and shorter processing times than can be achieved withagarose. Where the antibody comprises a C_(H3) domain, the BakerBondABX® resin is useful for purification.

Other techniques for protein purification, such as fractionation on anion-exchange column, ethanol precipitation, Reverse Phase HPLC,chromatography on silica, chromatography on heparin Sepharose®,chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are alsoavailable, and can be applied by one of skill in the art.

Following any preliminary purification step(s), the mixture comprisingthe antibody of interest and contaminants may be subjected to low pHhydrophobic interaction chromatography using an elution buffer at a pHbetween about 2.5 to about 4.5, generally performed at low saltconcentrations (e.g., from about 0 to about 0.25 M salt).

11. Pharmaceutical Compositions and Methods of Administration

Any of the antibodies provided herein can be provided in any appropriatepharmaceutical composition and be administered by any suitable route ofadministration. Suitable routes of administration include, but are notlimited to, the inhalation, intraarterial, intradermal, intramuscular,intraperitoneal, intravenous, nasal, parenteral, pulmonary, andsubcutaneous routes.

The pharmaceutical composition may comprise one or more pharmaceuticalexcipients. Any suitable pharmaceutical excipient may be used, and oneof ordinary skill in the art is capable of selecting suitablepharmaceutical excipients. Accordingly, the pharmaceutical excipientsprovided below are intended to be illustrative, and not limiting.Additional pharmaceutical excipients include, for example, thosedescribed in the Handbook of Pharmaceutical Excipients, Rowe et al.(Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

In some embodiments, the pharmaceutical composition comprises ananti-foaming agent. Any suitable anti-foaming agent may be used. In someaspects, the anti-foaming agent is selected from an alcohol, an ether,an oil, a wax, a silicone, a surfactant, and combinations thereof. Insome aspects, the anti-foaming agent is selected from a mineral oil, avegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, afatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, afatty acid ester, a silicon glycol, a fluorosilicone, a polyethyleneglycol-polypropylene glycol copolymer, polydimethylsiloxane-silicondioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethylalcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, andcombinations thereof.

In some embodiments, the pharmaceutical composition comprises acosolvent. Illustrative examples of cosolvents include ethanol,poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, andpropylene glycol.

In some embodiments, the pharmaceutical composition comprises a buffer.Illustrative examples of buffers include acetate, borate, carbonate,lactate, malate, phosphate, citrate, hydroxide, diethanolamine,monoethanolamine, glycine, methionine, guar gum, and monosodiumglutamate.

In some embodiments, the pharmaceutical composition comprises a carrieror filler. Illustrative examples of carriers or fillers include lactose,maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum,and guar gum.

In some embodiments, the pharmaceutical composition comprises asurfactant. Illustrative examples of surfactants include d-alphatocopherol, benzalkonium chloride, benzethonium chloride, cetrimide,cetylpyridinium chloride, docusate sodium, glyceryl behenate, glycerylmonooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol,phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitanfatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodiumlauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol)succinate.

In some embodiments, the pharmaceutical composition comprises ananti-caking agent. Illustrative examples of anti-caking agents includecalcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropylcellulose, and magnesium oxide.

Other excipients that may be used with the pharmaceutical compositionsinclude, for example, albumin, antioxidants, antibacterial agents,antifungal agents, bioabsorbable polymers, chelating agents, controlledrelease agents, diluents, dispersing agents, dissolution enhancers,emulsifying agents, gelling agents, ointment bases, penetrationenhancers, preservatives, solubilizing agents, solvents, stabilizingagents, and sugars. Specific examples of each of these agents aredescribed, for example, in the Handbook of Pharmaceutical Excipients,Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press,incorporated by reference in its entirety.

In some embodiments, the pharmaceutical composition comprises a solvent.In some aspects, the solvent is saline solution, such as a sterileisotonic saline solution or dextrose solution. In some aspects, thesolvent is water for injection.

In some embodiments, the pharmaceutical compositions are in aparticulate form, such as a microparticle or a nanoparticle.Microparticles and nanoparticles may be formed from any suitablematerial, such as a polymer or a lipid. In some aspects, themicroparticles or nanoparticles are micelles, liposomes, orpolymersomes. In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of one or moreprophylactic or therapeutic antibodies.

Further encompassed herein are anhydrous pharmaceutical compositions anddosage forms comprising an antibody, since water can facilitate thedegradation of some antibodies.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

11.1. Parenteral Dosage Forms

In certain embodiments, provided are parenteral dosage forms. Parenteraldosage forms can be administered to subjects by various routesincluding, but not limited to, subcutaneous, intravenous (includingbolus injection), intramuscular, and intraarterial. Because theiradministration typically bypasses subjects' natural defenses againstcontaminants, parenteral dosage forms are typically, sterile or capableof being sterilized prior to administration to a subject. Examples ofparenteral dosage forms include, but are not limited to, solutions readyfor injection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Excipients that increase the solubility of one or more of the antibodiesdisclosed herein can also be incorporated into the parenteral dosageforms.

11.2. Dosage and Unit Dosage Forms

In human therapeutics, the doctor will determine the posology which heconsiders most appropriate according to a preventive or curativetreatment and according to the age, weight, condition and other factorsspecific to the subject to be treated.

The amount of the antibody or composition which will be effective in theprevention or treatment of a disorder or one or more symptoms thereofwill vary with the nature and severity of the disease or condition, andthe route by which the antibody is administered. The frequency anddosage will also vary according to factors specific for each subjectdepending on the specific therapy (e.g., therapeutic or prophylacticagents) administered, the severity of the disorder, disease, orcondition, the route of administration, as well as age, body, weight,response, and the past medical history of the subject. Effective dosesmay be extrapolated from dose-response curves derived from in vitro oranimal model test systems.

In certain embodiments, exemplary doses of a composition includemilligram or microgram amounts of the antibody per kilogram of subjector sample weight (e.g., about 10 micrograms per kilogram to about 50milligrams per kilogram, about 100 micrograms per kilogram to about 25milligrams per kilogram, or about 100 microgram per kilogram to about 10milligrams per kilogram). In certain embodiment, the dosage of theantibody provided herein, based on weight of the antibody, administeredto prevent, treat, manage, or ameliorate a disorder, or one or moresymptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject'sbody weight. In another embodiment, the dosage of the composition or acomposition provided herein administered to prevent, treat, manage, orameliorate a disorder, or one or more symptoms thereof in a subject is0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg,0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg,1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to2.5 mg.

The dose can be administered according to a suitable schedule, forexample, once, two times, three times, or for times weekly. It may benecessary to use dosages of the antibody outside the ranges disclosedherein in some cases, as will be apparent to those of ordinary skill inthe art. Furthermore, it is noted that the clinician or treatingphysician will know how and when to interrupt, adjust, or terminatetherapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the antibodiesprovided herein are also encompassed by the herein described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. For example, the dosage administered tothe subject may be increased to improve the prophylactic or therapeuticeffect of the composition or it may be decreased to reduce one or moreside effects that a particular subject is experiencing.

In certain embodiments, treatment or prevention can be initiated withone or more loading doses of an antibody or composition provided hereinfollowed by one or more maintenance doses.

In certain embodiments, a dose of an antibody or composition providedherein can be administered to achieve a steady-state concentration ofthe antibody in blood or serum of the subject. The steady-stateconcentration can be determined by measurement according to techniquesavailable to those of skill or can be based on the physicalcharacteristics of the subject such as height, weight and age.

In certain embodiments, administration of the same composition may berepeated and the administrations may be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, or 6 months. In other embodiments, administration of thesame prophylactic or therapeutic agent may be repeated and theadministration may be separated by at least 1 day, 2 days, 3 days, 5days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months,or 6 months.

12. Therapeutic Applications

For therapeutic applications, the antibodies of the invention areadministered to a mammal, generally a human, in a pharmaceuticallyacceptable dosage form such as those known in the art and thosediscussed above. For example, the antibodies of the invention may beadministered to a human intravenously as a bolus or by continuousinfusion over a period of time, by intramuscular, intraperitoneal,intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial,intrathecal, or intratumoral routes. The antibodies also are suitablyadministered by peritumoral, intralesional, or perilesional routes, toexert local as well as systemic therapeutic effects. The intraperitonealroute may be particularly useful, for example, in the treatment ofovarian tumors.

The antibodies provided herein may be useful for the treatment of anydisease or condition involving CD39, such as cancer, autoimmune disease,and infection.

Any suitable cancer may be treated with the antibodies provided herein.Illustrative suitable cancers include, for example, acute lymphoblasticleukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma,anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, braintumor, bile duct cancer, bladder cancer, bone cancer, breast cancer,bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin,cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia(CLL), chronic myelogenous leukemia (CML), chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneousT-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer,ependymoma, esophageal cancer, esthesioneuroblastoma, fibroushistiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladdercancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor, gestational trophoblastic disease,glioma, head and neck cancer, hairy cell leukemia, hepatocellularcancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer,Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oralcavity cancer, liver cancer, lobular carcinoma in situ, lung cancer,lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma,Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancerwith occult primary, midline tract carcinoma involving NUT gene, mouthcancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosisfungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferativeneoplasm, nasal cavity and par nasal sinus cancer, nasopharyngealcancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer,oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer,papillomatosis, paraganglioma, parathyroid cancer, penile cancer,pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonaryblastoma, primary central nervous system lymphoma, prostate cancer,rectal cancer, renal cell cancer, renal pelvis and ureter cancer,retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome,skin cancer, small cell lung cancer, small intestine cancer, soft tissuesarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoidtumor, testicular cancer, throat cancer, thymoma and thymic carcinoma,thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvarcancer, and Wilms tumor.

Any suitable autoimmune disease may be treated with the antibodiesprovided herein. Illustrative suitable autoimmune diseases, or diseaseswith an autoimmune component, include, for example, acute disseminatedencephalomyelitis (ADEM), acute necrotizing hemorrhagicleukoencephalitis, Addison's disease, agammaglobulinemia, alopeciaareata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBMnephritis, antiphospholipid syndrome (APS), autoimmune angioedema,autoimmune aplastic anemia, autoimmune dysautonomia, autoimmunehepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency,autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmuneoophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmunethrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmuneurticarial, axonal & neuronal neuropathies, Balo disease, Behcet'sdisease, bullous pemphigoid, cardiomyopathy, Castleman disease, Celiacdisease, Chagas disease, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic recurrent multifocalostomyelitis (CRMO), Churg-Strauss syndrome, cicatricialpemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome,cold agglutinin disease, colitis, congenital heart block, coxsackiemyocarditis, CREST disease, essential mixed cryoglobulinemia,demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis,Devic's disease (neuromyelitis optica), discoid lupus, Dressler'ssyndrome, endometriosis, eosinophilic esophagitis, eosinophilicfasciitis, erythema nodosum, experimental allergic encephalomyelitis,Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis(temporal arteritis), giant cell myocarditis, glomerulonephritis,Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerlycalled Wegener's Granulomatosis), Graves' disease, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolyticanemia, Henoch-Schonlein purpura, herpes gestationis,hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgAnephropathy, IgG4-related sclerosing disease, immunoregulatorylipoproteins, inclusion body myositis, inflammatory bowel disease.interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneousconjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease(chronic), Meniere's disease, microscopic polyangiitis, mixed connectivetissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiplesclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica(Devic's), neutropenia, ocular cicatricial pemphigoid, optic neuritis,palindromic rheumatism, PANDAS (Pediatric Autoimmune NeuropsychiatricDisorders Associated with Streptococcus), paraneoplastic cerebellardegeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Rombergsyndrome, Parsonnage-Turner syndrome, pars planitis (peripheraluveitis), pemphigus, peripheral neuropathy, perivenousencephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritisnodosa, type I, II, & III autoimmune polyglandular syndromes,polymyalgia rheumatic, polymyositis, postmyocardial infarction syndrome,postpericardiotomy syndrome, progesterone dermatitis, primary biliarycirrhosis, rimary sclerosing cholangitis, psoriasis, psoriaticarthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure redcell aplasia, Raynauds phenomenon, reactive arthritis, reflexsympathetic dystrophy, Reiter's syndrome, relapsing polychondritis,restless legs syndrome, retroperitoneal fibrosis, rheumatic fever,rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiffperson syndrome, subacute bacterial endocarditis (SBE), Susac'ssyndrome, sympathetic ophthalmia, Takayasu's arteritis, temporalarteritis/giant cell arteritis, thrombotic disease, thrombocytopenicpurpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1diabetes, ulcerative colitis, undifferentiated connective tissue disease(UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, andWegener's granulomatosis (now termed Granulomatosis with Polyangiitis(GPA).

Any suitable infection may be treated with the antibodies providedherein. Illustrative suitable infections include, for example, hepatitisA virus, hepatitis B virus, hepatitis C virus (HCV), humanimmunodeficiency virus (HIV), and other viral infections.

13. Diagnostic Applications

In some embodiments, the antibodies provided herein are used indiagnostic applications. For example, an ant-CD39 antibody may be usefulin assays for CD39 protein. In some aspects, the antibody can be used todetect the expression of CD39 in various cells and tissues. These assaysmay be useful, for example, evaluating cancer and autoimmune disease.

In some diagnostic applications, the antibody may be labeled with adetectable moiety. Suitable detectable moieties include, but are notlimited to radioisotopes, fluorescent labels, and enzyme-substratelabels. In another embodiment of the invention, the anti-CD39 antibodyneed not be labeled, and the presence thereof can be detected using alabeled antibody which specifically binds to the anti-CD39 antibody.

14. Affinity Purification Reagents

The antibodies of the invention may be used as affinity purificationagents. In this process, the antibodies may be immobilized on a solidphase such a resin or filter paper, using methods well known in the art.The immobilized antibody is contacted with a sample containing the CD39protein (or fragment thereof) to be purified, and thereafter the supportis washed with a suitable solvent that will remove substantially all thematerial in the sample except the CD39 protein, which is bound to theimmobilized antibody. Finally, the support is washed with anothersuitable solvent, such as glycine buffer, pH 5.0, that will release theCD39 protein from the antibody.

15. Kits

In some embodiments, an anti-CD39 antibody provided herein is providedin the form of a kit, i.e., a packaged combination of reagents inpredetermined amounts with instructions for performing a procedure. Insome embodiments, the procedure is a diagnostic assay. In otherembodiments, the procedure is a therapeutic procedure.

In some embodiments, the kit further comprises a solvent for thereconstitution of the anti-CD39 antibody. In some embodiments, theanti-CD39 antibody is provided in the form of a pharmaceuticalcomposition.

Examples Example 1: Selection of CD39 Antigen-Binding Proteins

CD39 ABPs were selected from a synthetic library of human antibodiespresented on the surface of yeast cells in IgG format, as generallydescribed, e.g., in WO2009036379; WO2010105256; WO2012009568; and Xu etal., Protein Eng. Des. Sel., 2013, 26:663-670 (each incorporated byreference in its entirety), and more specifically as provided below. Thesequences and characteristics of the ABPs isolated from the recombinantlibrary are provided in Table S.

Eight naïve human synthetic yeast libraries each of ^(˜)10 E+09diversity were propagated as described in WO2009036379; WO2010105256;WO2012009568; and Xu et al., Protein Eng. Des. Sel., 2013, 26:663-670;each incorporated by reference in its entirety. For the first two roundsof selection, a magnetic bead sorting technique utilizing the MiltenyiMACS® system was performed, as described in Siegel et al., J. Immunol.Meth., 2004, 286:141-153. The following rounds of selection wereperformed using flow cytometry based sorting. For all round ofselection, the antigen was biotinylated human CD39 extracellular domain(heretofore “ECD”), and decreasing concentrations of antigen were usedin each subsequent round of selection. In addition to selection onantigen, some rounds of selection were employed in order to reduce thenumber of non-specific binders utilizing soluble membrane proteins fromCHO cells (see WO2014179363 and Xu et al., Protein Eng. Des. Sel., 2013,26:663-670, each incorporated by reference in its entirety). After thefinal round of sorting, yeast were plated and individual colonies werepicked for characterization and for nomination of clones for affinitymaturation.

Antibody variable domains of interest were synthesized, with codonoptimization to maximize transient expression in host cells. Thevariable regions were cloned in to expression vectors containing humanimmunoglobulin constant domains and their sequence confirmed. Antibodyheavy and light chain vector pairings were transfected into Expi293cells using the Expifectamine system (Invitrogen). Transient cultureswere harvested on day 4 and clarified cell culture supernatant IgG titerwas estimated using Bio-Layer Interferometry (BLI) using Octet(ForteBio) alongside standards. Antibodies were subsequently purified ona Protein A column and eluted using low pH glycine. Purified antibodysamples were then buffer-exchanged or dialyzed into downstreamassay-compatible buffers.

Antibody purity was assessed by running samples on SDS-PAGE and on ananalytical size exclusion chromatography column.

Light Chain Shuffling: Heavy chain plasmids were extracted from naïveoutputs (described herein) and transformed into a pre-made naïve lightchain library with a diversity of 10E+06. Selections were performed asdescribed above with one round of MACS sorting and three rounds of FACSsorting using decreasing amounts of biotinylated ECD antigen forrespective rounds. Selected individual heavy chains from the primarydiscovery process were also independently transformed into separatepre-made light chain libraries with a diversity of 10E+06 and selectionsperformed as described above with one round of MACS sorting and threerounds of FACS sorting using decreasing amount of biotinylated ECDantigen for respective rounds.

Example 2: Affinity Maturation

Optimization of naïve clones was carried out utilizing three maturationstrategies; diversification of CDR-H1 and CDR-H2; diversification ofCDR-H3; diversification of CDR-L1, L2 and L3; shuffling of diversifiedheavy and light chains.

CDR-H1 and CDR-H2 Selection: The CDR-H3s from clones selected from eachof the light chain batch diversification, light chain diversification,and naïve discovery efforts were independently recombined into premadelibraries with CDR-H1 and CDR-H2 variants of a diversity of >10E+8 andselections were performed using ECD antigen. Affinity pressures wereapplied by using decreasing concentrations of antigen.

CDR-H3 Selection: Clones obtained from the CDR-H1 and CDR-H2 selectionprocedure were subject to additional rounds of affinity maturation viawalking dimer mutagenesis of the heavy chain. Selections were performedusing ECD as antigen generally as described above but with the additionof employing FACS sorting for all selection rounds.

CDR-L1, L2, L3 Selection: Clones obtained from the CDR-H1 and CDR-H2selection procedure were subject to additional rounds of affinitymaturation via mutagenesis of the light chain. The CDR-L1 and CDR-L2diversity derived from a pre-made library while CDR-L3 diversity derivedfrom walking dimer mutagenesis. Selections were performed using ECD asantigen generally as described above but with the addition of employingFACS sorting for all selection rounds, with one round of MACS followedby three rounds of FACS in the CDR-L1, L2, L3 process described here.

Diversified Heavy Chain and Light Chain Shuffling: Outputs from heavychain diversification and light diversification described above wererecombined and selections were performed using ECD as antigen generallyas described above but with the addition of employing FACS sorting forall selection rounds.

Example 3: Monovalent Affinity of Anti-hCD39 Antibodies to RecombinantCD39 Extracellular Domain

Binding kinetics were measured using the Octet Red96 system (ForteBio)at 25° C. in running buffer (lx Pall ForteBio Kinetics Buffer dilutedinto PBS or Tris pH 7.4). In brief, 1.25 mg/ml of unlabeled anti-hCD39antibodies were immobilized onto anti-human Fc sensors. After a shortbaseline step in running buffer, the sensors were exposed to varyingconcentrations (10-300 nM) of rhCD39-ECD-His (R&D Systems) for theassociation step. Dissociation of the complex was monitored uponexposure of the sensors to running buffer once again. Data was processedusing ForteBio Octet software with baseline subtraction, global fit and1:1 binding model to obtain association and dissociation rates. K_(D)was calculated from the ratio of k_(d) to k_(a).

Data shown in FIG. 1 had R²>0.980. PF=poor fit. The association anddissociation time course data was globally fit with a simple 1:1Langmuir binding model to yield on-rate (kon) and off-rate (koff)values. The equilibrium dissociation constants (K_(D)) were calculatedfrom the kon and koff values. The kon values ranged from 1.93E+04 to1.72E+06 M⁻¹s⁻¹ and the off rate values ranges from 3.65E-01 to 1.11E-04s⁻¹. The K_(D) values ranged from 4.09E-07 to 7.31E-011 molar indicatingthat all of the antibodies bound with moderate or high affinity to humanCD39 ECD.

The paralog specificity of the anti-CD39 antibodies was assessed bybiolayer interferometry using soluble recombinant human ENTDP2 andsoluble recombinant human ENTDP3 (both from R&D Systems). ENTDP2 andENTDP3 are enzymes with functions similar to CD39. None of theantibodies exhibited detectable binding to ENTDP2 or ENTDP3 (data notshown). Thus all of the antibodies exhibit specific binding to humanCD39.

Example 4: Inhibition of Recombinant Human CD39 Extracellular Domain

The inhibition of recombinant human CD39 ECD by anti-CD39 antibodies wasmeasured as follows. Recombinant human CD39/ENTPD1 (4397-EN from R&Dsystems), (either 5 or 10 nM final concentration) was combined withanti-CD39 IgGs (0.25 or 1 micromolar final concentration) in 25 mM Tris,5 mM CaCl₂, pH 7.5 in a 96-well plate and incubated at room temperaturefor 2 hrs. ATP (Sigma A1852-1VL) was then added to a final concentrationof 500 micromolar and incubated at 37° C. for 60 minutes. The plate wasthen placed at room temperature and CellTiter-Glo Luminescent CellViability Assay solution was added to each well of the assay plate,mixed and read on a microplate reader using “CellTiter-Glo luminescent”preset. Control reactions consisting of negative control IgG, IgG only(no ATP), ATP only (no CD39) were run using the same method. Data valuesare the average of 2 replicates.

Inhibition of human CD39 ECD enzymatic activity by anti-CD39 antibodieswas determined by measuring ATP levels using the CellTiter-Glo assay(FIGS. 2 A-E). The enzymatic catabolism of ATP by CD39 ECD was observedin the presence of an isotype control antibody or no IgG with averageRLU values ranging from 38 to 857. All of the anti-CD39 antibodiesshowed marked inhibition ATP catabolism by CD39, having much higheraverage RLU values than the isotype control antibody (average RLU valuesrange from 4890 to 20329). In contrast, Benchmark antibody BY40va didnot show significant inhibition of CC39 ECD in this assay having RLUvalues similar to the isotype control antibody (average RLU values 11and 415).

Example 5: Antibodies Bind to CHO Cells Expressing Human and Cyno CD39

Binding of anti-CD39 IgGs to Chinese Hamster Ovary K1 (CHO) CD39 cells.100 nanomolar IgGs (each antibody is indicated as a unique clone numberin the FIG.) were incubated at 25° C. for 30 minutes on ice in phosphatebuffered saline (PBS) with parental CHO cells or CHO cells engineered toexpress either human or cynomolgus macaque (Macaca fascicularis) CD39(CHO CD39 cells). Cells were then washed with ice cold PBS and incubatedwith a fluorescently labeled goat-anti-human IgG for 20 minutes on ice.Cells were washed and resuspended in ice cold PBS prior to analysis byflow cytometry. Fold over background binding levels represent the ratioof median fluorescence intensity (MFI) values for anti-CD39 antibodiesbinding to CHO CD39 to MFI values for anti-CD39 antibodies binding tothe parental CHO cells.

The anti-CD39 antibodies bound to CHO cells expressing cellular humanCD39 (CHO CD39 cells) and did not exhibit significant binding toparental CHO cells (FIGS. 2F-J). The binding of these antibodies to CHOCD39 cells ranged from 10 to 2033-fold over background. Antibodies 28337and 27575 did not show significant binding to CHO CD39 cells (only 2 to4-fold over background) (FIGS. 2F-J) indicating that these antibodies donot have low affinity for the cellular form of human CD39.

The ortholog specificity of the anti-CD39 antibodies was assessed withflow cytometry using CHO cells engineered to express either cynomolgusmacaque or mouse CD39. The anti-CD39 antibodies bound to cynomolgusmacaque CD39 to a similar extent as human CD39 (FIGS. 2 F-J). None ofthe anti-CD39 antibodies showed detectable binding to mouse CD39. Thus,the anti-CD39 antibodies are cross reactive to cynomolgus macaque CD39but not to mouse CD39.

Example 6: Binding of Antibodies to Cell Surface CD39 in MEL-28 or 721Cells and Antibodies that Inhibit CD39 on MEL-28 Cells a Short TermATPAse Assay

Cells were incubated with serially diluted anti-CD39 antibodies for 30minutes at 4 degrees C. Cells were washed 3 times in FACS buffer (PS, 2%FBS, and 2 mM EDTA) and next incubated with secondary antibody (goatanti-human IgG Southern Biotech) at 1:100 for 30 minutes at 4 degrees C.Cells were washed, resuspended in FACS buffer, and analyzed for bindingby flow cytometry analysis on BD Celesta.

3.5×10⁴ MEL-28 cells/well were washed with Tris buffer and incubatedwith serially diluted (100-0.00013 nM) antibody for 30 minutes at 37degrees C. 50 μM ATP was added to each well and incubated with cells for15 minutes. The supernatants were collected and analyzed in MalachiteGreen Assay (R&D) according to manufacturer's protocol. Phosphatereleased from CD39 processing of ATP was used as a readout of enzymeactivity. Palivizumab was used as an isotype control and ARL (Tocris)and POM-1 (Alpha Aesar), non-specific small molecule inhibitors of CD39,were used as positive controls at 100 μm.

All antibodies bound to endogenously expressed CD39 on both cell lineswith similar affinity with EC50 ranges from 0.05-0.28 μg/ml on MEL-28(see FIG. 3 A) and with EC50 ranges of 0.2-7.5 μg/ml on 721.22 cell line(see FIG. 3B). Maximum signal (MFI) differed between antibodies testedeven when EC50 values were similar (FIGS. 3A-B).

After confirmation of cellular binding, anti-CD39 antibodies wereevaluated for inhibition of ATPase activity on MEL-28 cell in short term30 minute Malachite Green phosphate readout assay. Isotype control wasused to establish maximum possible signal from ATP processing in MEL-28cells-50 μm ATP addition to cells typically resulted in 55-60 μMphosphate signal in this assay (see FIGS. 4A and B). Anti-CD39antibodies inhibited ATPase activity in MEL-28 cells by 60-80% at thehighest concentration of antibodies tested (100 nM)—this level ofinhibition was similar to non-specific ATPase inhibitors ARL and POM1(see FIG. 4A). IC50 values for anti-CD39 antibodies in MEL-28 malachitegreen assay were all in sub-nanomolar range (see FIG. 4B).

Example 7: ATP Preservation Quantified when MEL-28 Cells are Treatedwith CD39 Enzymatic Inhibitors

3.5×10⁴ MEL-28 cells were plated overnight at 37 degrees C. Cells werewashed with Tris assay buffer to remove phosphate. 100 nM titrated downto 0.005 pM of monoclonal antibodies were incubated with cells for 30minutes at 37 degrees C. 50 μM ATP was added and incubated for 15minutes. Supernates were harvested and frozen. Supernates were thawedand evaluated for ATP using the EnzyLight (EnzyLight ATP Assay Kit,BioAssay Systems). Palivizumab was used as an isotype control and ARL(Tocris) and POM-1 (Alpha Aesar) used at a concentration of 100 μM arenon-specific small molecule inhibitors of CD39 as positive controls.

ATP was almost undetectable after 30 minutes post ATP addition to thecells in untreated and/or isotype treated samples (see FIG. 5 A) whileall of the anti-CD39 antibodies tested prevented processing of ATP indose dependent manner (see FIG. 5A, B). Most of the anti-CD39 antibodiestested in this assay prevented ATP processing by CD39 to a similarextent as ARL (see FIG. 5A). IC50s of anti-CD39 antibodies in ATPpreservation assay ranged from 0.02-0.1 nM. Overall potency ofantibodies in this assay was consistent with what was observed inMalachite Green phosphate readout assay.

Example 8: Antibodies Inhibit CD39 Activity on MEL-28 in an OvernightAssay

3.5×10⁴ MEL-28 cells/well were plated and incubated with antibodiesovernight at 37 degrees C. Cells were washed to remove FBS. Cells nextwere pre-treated with antibodies in X-VIVO 15 FBS free media overnightat 37 degrees C. ATP was then spiked in at 50 μM for 15 minutes.Supernatants were collected and analyzed using AMP-Glo kit according tomanufacturer's instructions (Promega). Palivizumab was used as anisotype control and POM-1 (Alpha Aesar), a non-specific small moleculeinhibitor of CD39, was used as positive control at 100 μM.

Anti-CD39 antibodies tested in overnight AMPGlo assay in MEL-28 cellsdemonstrated sustained inhibition of ATPase activity as indicated bydecreased AMP levels present in the supernatants (see FIG. 6A).Inhibition of CD39 activity by antibodies was equivalent to or morepotent compared to POM-1 treatment. The data is consistent with resultsobtained in CD39 short-term Malachite Green assay in MEL-28 (see FIG.4). Antibodies tested in an overnight assay had IC50 values in an AMPGloCD39 inhibition assay ranging from 0.01 to 0.3 nM. (see FIG. 6 B)

Example 9: Anti-CD 39 Antibodies Bind to Primary Human and Cyno B Cells

B cells were isolated from human donor leukopak using EasySep B cellisolation kit (STEMCELL Technologies). Cyno monocytes were purified fromfresh cyno blood using NHP CD14 positive selection kit (Miltenyi) andflow through was collected and stained with CD4, CD8, CD20, CD16, andCD3 antibodies (BD). Human B cells or cyno cells were incubated withserially diluted anti-CD39 antibodies (15 μg/ml 7.5 fold serialdilution, 8-point) for 30 minutes at 4 degrees C. Cell were washed 3times in FACS buffer (PS, 2% FBS, and 2 mM EDTA) and incubated withsecondary antibody (mouse anti-human IgG southern biotech) at 1:100 for30 minutes at 4 degrees C. Cells were washed 2 times in FACS buffer andresuspended in FACS buffer and analyzed on BD Celesta.

Detection of antibody binding is as described in FIG. 7 where B cellswere incubated with serially diluted antibodies and detected using afluorescently tagged antibody and analyzed by flow cytometry. Theresults are shown in FIG. 7 and appear to indicate that the antibodiesbind specifically to both human and cyno B cells with EC50s that rangefrom 0.02 μg/ml to 3.18 μg/ml (human) and 0.03 μg/ml to 0.17 μg/ml(cyno). Similar binding was observed on human tumor cells lines (FIG. 3)where subset of the antibodies had a low maximal MFI and a subset had ahigh MFI to both the human and cyno B cells.

Example 10: Antibodies Inhibit CD39 Activity on Human B Cells

B cells were isolated from human leukopak using EasySep B cell isolationkit (STEMCELL Technologies). 5×10⁴ B cells/well were washed with Trisbuffer and incubated with serially diluted (100-0.00013 nM) antibodiesfor 30 minutes at 37 degrees C. 50 μM ATP was added to each well andincubated with cells for 2 hrs. The supernatants were collected andanalyzed in Malachite Green Assay (R&D) according to manufacturer'sprotocol. Phosphate released from CD39 processing of ATP was used as areadout of enzyme activity. Palivizumab was used as an isotype controland ARL (Tocris) and POM-1 (Alpha Aesar), non-specific small moleculeinhibitors of CD39, were used as positive controls at 100 μM.

The antibodies were demonstrated to bind to primary human and cyno Bcells (see FIG. 7) and the next step was to evaluate the inhibition ofATP hydrolysis by detection of free phosphate (Pi) using a malachitegreen assay. The results are shown in FIG. 8 and indicate the anti-CD39antibodies inhibit the enzymatic inhibition/dephosphorylation of ATP byprimary human B cells. The ability of the antibodies to inhibitenzymatic activity was comparable regardless of high vs. low max MFIdetected in the binding to human B cells (FIG. 7).

Example 11: Anti-CD39 Antibodies Inhibit ATPAse Activity on Human andCyano Monocytes

Human monocytes were purified from leukopak using EasySep Humanmonocytes isolation kit (STEMCELL). Cyno monocytes were isolated fromwhole cyno blood using NHP CD14 positive selection kit (Miltenyi).Monocytes at 5×10⁴ cells/well were washed with Tris buffer and incubatedwith serially diluted (100-0.00013 nM) anti-CD39 antibodies for 30minutes at 37 C. 50 μM ATP was added to the cells for 15 minutes at 37 Cand supernatants were harvested and analyzed in Malachite Green Assay(R&D) for phosphate levels. Palivizμmab was used as an isotype controland ARL (Tocris) and POM-1 (Alpha Aesar), non-specific small moleculeinhibitors of CD39, were used as positive controls at 100 μM.

CD39 expression has been detected on human leukocytes with the highestexpression detected on monocytes (Thromb Res. 2007; 121(3):309-17).Because of this information, it was important to evaluate the ability ofthe anti-CD39 antibodies to inhibit ATPase activity on the cell surface.As demonstrated in FIG. 7, anti-CD39 antibodies bind to both human andcyno B cells. It is appropriate to evaluate the inhibition of enzymaticactivity on human and cyno monocytes. The results indicate that all theantibodies are able to inhibit ATPase activity of CD39 on human and cynomonocytes with similar potencies.

Example 12: Anti-CD39 Antibodies Bind to Primary Human TRegs and InhibitCD39 Enzymatic Activity

Treg cells were isolated from human donor leukopak usingCD4⁺CD25⁺CD127^(dim) regulatory T cell isolation kit II (Miltenyi).Human Treg cells were incubated with serially diluted anti-CD39antibodies (100 nM-0.00064 nM) for 30 minutes at 4 degrees C. Cell werewashed 3 times in FACS buffer (PS, 2% FBS, and 2 mM EDTA) and incubatedwith secondary antibody (mouse anti-human IgG southern biotech) at 1:100for 30 minutes at 4 degrees C. Cells were washed 2 times in FACS buffer,resuspended in FACS buffer and analyzed on BD Fortessa.

CD4⁺CD25⁺CD127^(dim) human Treg cells were washed 3× with Tris buffer.Cells were incubated with anti-CD39 antibodies (100 nM-0.00064 nM) for30 minutes at 37 C. The cells were spiked with 50 μM ATP andsupernatants were collected after 15 minutes incubation at 37 C.Supernatants were analyzed for phosphate levels in Malachite Green Assaykit (R&D). Palivizumab was used as an isotype control and ARL (Tocris)and POM-1 (Alpha Aesar), non-specific small molecule inhibitors of CD39,were used as positive controls at 100 μM.

CD39 had been shown to be expressed on human regulatory T cells (Treg)and important for their suppressive function by hydrolysis of ATP toimmune suppressive adenosine. (Blood. 2007 Aug. 15; 110(4):1225-32,Cellular & Molecular Immunology (2017) 14, 521-528;doi:10.1038/cmi.2016.30). In order to determine whether the anti-CD39antibodies were capable of inhibiting CD39 enzymatic activity, it wasimportant to evaluate the binding to human Tregs. Tregs were isolatedfrom human PBMCs and the Tregs were purified and the anti-bodies wereevaluated for binding by flow cytometry. The result indicate that theanti-CD39 antibodies bind to human Tregs (FIG. 10). Of note, both thehigh maximum MFI and low MFI profiles were observed similar to the humanB cell staining (see FIG. 8). The ability of the antibodies to inhibitthe ATPase activity on human Tregs was also evaluated. All theantibodies inhibit Treg CD39 enzymatic activity (see FIG. 11) equallywell regardless of the maximal MFI staining observed.

Example 13: Anti-CD39 Antibodies Increase CD8⁺ T Cell Response in a CMVRecall Response Assay

Frozen PBMCs are thawed and resuspended at 3×10⁶/ml and cultured inpresence of CMV peptides (Miltenyi, PeptTivator CMV pp65) for 3 days incomplete (10% FBS) media at 37 degrees C. T cells were then purified(STEMCELL, EasyStep) and rested for 24 hours at 37 degrees C. APCs weregenerated by depleting CD2 positive cells (STEMCELL, Easystep) fromPBMCs from the same donor and plated at 5×10⁴/well overnight at 37degrees C. The following day 5×10⁴ rested T cells were added to theAPCs. Antibodies were added at 25 μg/ml plus 100μ M ATP+1 μM EHNA andGolgi plug/stop with CMV peptides and incubated at 37 degrees C. for 5hours. T cells were stained and analyzed for intracellular IFN gamma ona Fortessa (Becton Dickinson) flow cytometer.

Adenosine has been shown to inhibit T cell activation. (Int J Oncol.2008 March; 32(3):527-35). As the rate-limiting enzyme inATP/ADP-AMP-adenosine pathway, inhibiting CD39 would diminish the levelsof immune suppressive adenosine and increase immune activating ATPresulting in enhanced T cell activity. In order to evaluate the role ofanti-CD39 antibodies inhibiting ATP/ADP-AMP hydrolysis, preventing thegeneration of adenosine which could result in an increased T cellresponse, a CMV recall assay was used. PBMCs were cultured in thepresence of a pool of CMV peptides for 3 days and then the T cells werepurified cultured with autologous PBMC plus CMV peptides and ATP+EHNA.After 5 hours the T cells were evaluated for the production of IFNgamma. The results indicate that some of the anti-CD39 antibodies wereable to increase CD8⁺ T cells activity in a CMV recall responses assay.This demonstrates that inhibiting the enzymatic activity of CD39prevents the generation of adenosine and preserves ATP levels andallowing for a robust T cell response to a peptide:MHC complex. Inaddition, not all antibodies that bind to CD39 and inhibit cell surfaceenzymatic activity are capable of increasing T cell response and thespecific interaction of the antibody to CD39 is important.

Example 14: Evaluation of Antibodies for Inhibition of CD39 Activity onMel-28 and Human Monocytes

3.5×10⁴ MEL-28 cells/well were incubated with 100 nM down to 0.32 pM ofmonoclonal antibodies for 30 minutes. 50 μM ATP was added and incubatedfor 15 minutes. Supernate was evaluated for free phosphate (Pi) usingthe Malachite Green Phosphate Detection Kit (R&D Systems cat#DY996).Palivizumab was used as an isotype control and ARL (Tocris) and POM-1(Alpha Aesar) used at a concentration of 100 μM as non-specific smallmolecule inhibitors of CD39 as positive controls. Cyno monocytes wereisolated from whole cyno blood using NHP CD14 positive selection kit(Miltenyi). Monocytes at 5×10⁴ cells/well were washed with Tris bufferand incubated as described above.

When comparing anti-CD39 antibodies for enzymatic inhibition in shortterm assays, differences were observed. Some were able to block therelease of free phosphate (Pi) measured in a malachite green assay andothers demonstrated very little activity. For example, BY40v9 and 9-8Bhave little to no enzymatic inhibition at concentrations of 100 nM usingboth the MEL-28 cell or primary human monocyte compared to otheranti-CD39 antibodies (e.g., 29579 and 28347) that are able to inhibitATPase activity at low nM concentrations.

9-8B was produced as described in US 2017/0335007 A1, using SEQ ID Nos.22 and 23, as hIgG4. BY40v9 is an engineered variant of the antibodyBY40 described in WO 2009/095478 A1 SEQ ID Nos. 1 and 5. We tried toexpress BY40 as described as a human IgG4 but repeated attempts failed.The VH described in SEQ No.1 appears to be missing several N-terminalresidues compared to germline VH's, so we engineered in the missingresidues with closest germline sequence from IMGT (http://imgt.org/),resulting in BY40-v9, which expressed and was determined to specificallybind rhCD39-ECD and cellular ECD.

Example 15: Design of Chimera and Region of Distinct Binding

(a) Examples of Antibodies that Bind Soluble Recombinant CD39 ECD andCellular CD39 but do not Inhibit ATPase Activity and do not Compete withCellular Inhibitors for Binding to ECD Inhibitors

0.04-3.3 nM rhCD39-ECD (R&D Systems) was incubated with buffer, 50 μg/mlantibody or 100 μM POM-1 (Alpha Aesar) for 1 hr at 37° C. in assaybuffer (25 mM Tris pH 7.5, 5 mM CaCl₂) at which point ATP (Sigma) wasspiked in to a final concentration of 10 μM, and the reaction furtherincubated for 30 min 37° C. Production of free phosphate (Pi) wassubsequently measured using Malachite Green Phosphate Detection kit (R&DSystems).

Indicated cells were incubated in assay buffer with 10-25 μg/mlantibody, 100 μM POM-1 or 100 μM ARL for 30 min at 37° C. 5% CO₂. ATPwas added to a final concentration of 50 μM and the incubation continuedfor 15 min. Supernatant was evaluated for free phosphate (Pi) using theMalachite Green Phosphate Detection kit. Palivizumab is used as anisotype control and POM-1 and ARL are non-specific small moleculeinhibitors of CD39.

A1 antibody was immobilized onto an Anti-Mouse IgG Fc Capture (AMC)biosensor (ForteBio). Association of hCD39-ECD was then monitored for180 seconds via Bio-Layer Interferometry (BLI) using the Octet system(ForteBio), at which point the biosensor was dipped into competitorantibody and monitored for another 180 seconds. Association of thesecond antibody was recorded as an upward shift in the interferencepattern and indicates that the antibodies bind to different epitopes onCD39. No change in the interference pattern indicated that A1 blocks thesecond antibody from binding to CD39.

Although A1 does bind hCD39 ECD (FIG. 1), it does not inhibit its ATPaseactivity. Although A1 does bind cellular CD39 (FIG. 2), it does notappreciably directly inhibit the ATPase activity of CD39 expressed onOAW42. Capture of hCD39 ECD by A1 blocks subsequent binding by A1 (FIG.14A, bottom right hand sensorgram), but does not block binding ofinhibitory antibodies such as 27536, 27571, 27579, 27597, or 38347.

The commercially available A1 antibody represents a group of anti-humanCD39 monoclonal antibodies that do not directly inhibit the ATPaseactivity of CD39 and do not bin with any of the other anti-CD39antibodies described here. More than 30 antibodies were discovered thatdo not inhibit ECD ATPase activity, do not inhibit cellular CD39 ATPaseactivity, but do compete with A1 for binding to ECD. These antibodiesmay be considered to bin with anti-hCD39 antibody A1.

(b) Example of Antibodies that have Limited Ability to Inhibit theATPase Activity of Both Soluble Recombinant and Cellular CD39 and BinSeparately from Other Cellular CD39 Inhibitors

The methods are the same as set forth above except that instead of A1,the representative antibody was immobilized using anti-human IgG FcCapture (AHC) biosensor.

Anti-hCD39 antibodies exemplified by 27536 and 28337 represent a groupof antibodies that bind both soluble ECD and cellular CD39 and have theability to inhibit their ATPase activity yet do not compete with otherinhibitors for CD39 binding. Both 27536 and 28337 are able to inhibitthe hydrolysis of ATP by hCD39 ECD compared to isotype or buffercontrols as shown by μM Pi, as described herein (top left panel). 27536and 28337 inhibit the hydrolysis of CD39 expressed on MEL-28 and OAW42cells, as shown, compared to isotype control. Antibodies 27536 and 28337represent a distinct bin group of anti-hCD39 inhibitory antibodies sincethey are blocked from binding CD39 ECD by another bin member that doesnot block other inhibitory antibodies such as 27571, 27579, 27597, or38347 (see insert (c) at the bottom of FIG. 14B).

(c) Example of Antibodies that Inhibit the ATPase Activity of SolubleRecombinant CD39ECD but do not Inhibit Cellular CD39 and Bin Separatelyfrom Other CD39 ECD Inhibitors

The methods are as provided above, with the addition of experimentaldesign where inhibition of 0.37 nM CD39 by 50 μg/ml antibody waschallenged by ATP concentrations of 3-100 μM. Also, an 18 hourincubation was used with the antibody or isotype control. Finally, anadditional 30 second baseline dip in buffer between antigen capture anddipping into a second competitor antibody for 300 seconds was used.

Anti-hCD39 antibodies exemplified by 27549 represent a group ofantibodies that can bind ECD and cellular CD39 but can only inhibit ECDATPase activity and not cellular CD39 ATPase activity. As can be seen inFIG. 14C (top left), 27549 is able to inhibit the hydrolysis of ATP byhCD39 ECD compared to isotype or buffer controls. Also from FIG. 14C(top right), 27549 is unable to inhibit the hydrolysis of CD39 expressedon MEL-28 cells compared to isotype control. Antibodies 27536 and 28337represent a distinct bin group of anti-hCD39 inhibitory antibodies sincethey are blocked from binding CD39 ECD by another bin member that doesnot block other inhibitory antibodies such as 27571, 27579, 27597, or38347 (see FIG. 14C, bottom).

Antibody 27549 represents a group of anti-human CD39 monoclonalantibodies that directly inhibit the ATPase activity of sol CD39 ECD yetdoes inhibit cellular CD39 despite being able to bind to CD39 expressedon cells (FIG. 2). It does not compete with A1 or with any of the otherinhibitory anti-CD39 antibodies described here for binding to ECD, so27549 represents another bin of anti-hCD39 antibodies (see FIG. 14C).

(d) Example of Antibodies that Inhibit the ATPase Activity of ECD andCellular CD39 and Bin Separately from Other CD39 ECD and/or CellularInhibitors

The methods are as provided above.

Antibodies 27571, 27579 and 28347 represent a group of anti-human CD39antibodies that directly inhibit the ATPase activity of soluble CD39 ECDand inhibit cellular CD39 and yet do not compete with A1, cellularinhibitors 27536 or 28337, or ECD inhibitor 27549 (FIGS. 14A-C) forbinding to ECD. 27571, 27579, and 28347 are able to inhibit thehydrolysis of ATP by hCD39 ECD compared to isotype or buffer controls(see FIG. 14D, left). 27571, 27579, and 28347 also inhibit thehydrolysis of CD39 expressed on MEL-28 cells compared to isotype control(see FIG. 14D, right). These cellular inhibitors represent another binof anti-hCD39 antibodies (see FIG. 14D).

(e) Examples of Inhibitory Antibodies that Make Distinct Contacts withCD39

Chimeras were generated by replacing human CD39 with mouse CD39 sequencein mammalian expression vectors. The chimeras were expressed in CHOcells and the ability of anti-human CD39 antibodies to bind the chimerastested via FACS. In brief, cells were washed and blocked in FACS buffer(PBS/2% FBS) for 30 min on ice. They were then incubated with 15 μg/mlanti-human CD39 antibodies diluted in FACS buffer×1 h on ice. After 2washes, cells were incubated with fluorescently labeled anti-human Fcantibodies, anti-mouse Fc antibodies, or anti-mCD39 antibody (R&DSystems 495826) diluted in FACS buffer per manufacturers'instructions×30 min on ice. After 2 washes, cells were resuspended inFACS buffer and analyzed on BD Fortessa. Data was processed with FlowJo.Positive binding was scored as “yes” and lack of binding was scored as“NO” and examples of FACS plots used to generate this table are in FIGS.14.F and 14.G.

Chimeras formed between human and mouse CD39 distinguish regionscritical for antibody contact that are unique to inhibitory antibodiessuch as 31414, 31895, 31873, 31901, 31905, reference antibodies such asBY40v9 and 9-8B, and commercial antibodies such as A1 and 498403.Columns 1 and 3 describe the human CD39 sequences flanking the mouseCD39 sequence described in column 2. Column 4 lists the exact mouseamino sequence in the chimera.

The antibodies described thus far have no/minimal cross-reactivity tomouse CD39, which shares 78% percent identity with human CD39 in theextracellular domain. Chimeras were therefore made between human andmouse CD39 in order to identify those region(s) critical to antibodyrecognition and binding. To that end, 8 chimeras were generated with thesequence swaps chosen based on sequence diversity between human andmouse CD39 and potential for surface exposure based on rat ENTPD1 andrat ENTPD2 crystal structures. Thus, these 8 chimeras do notcomprehensively interrogate all potential contact residues. All testedantibodies were able to bind Chimeras #1,3,5,6,7, and 8, suggesting thatthese chimeras maintained overall global structural integrity. A1 and498403 lost the ability to bind Chimera #4, indicating that residuescritical to their contact with human CD39 had been lost. A1, 498403,BY40v9 and 9-8B were able to bind Chimera #2, suggesting that thischimera maintained overall global structural integrity. In contrast,inhibitory antibodies 31414, 31895, 31901, 31905, and 31873 were able tobind all chimeras but Chimera #2. Thus, Chimera #2 has lost residuescritical to making contacts with these antibodies and thereforeE143-N158 constitute part or all of the human CD39 epitope for theseantibodies. Notably, these antibodies belong to the bin groupexemplified by 27571, 27579 and 28347 in FIG. 14D, i.e. they do not binwith anti-CD39 antibody bin groups represented by antibodies A1, 27536,or 27549.

Chimeras were generated by mutagenesis of Chimera #2 or WT hCD39expression vectors. Residues for mutagenesis were chosen based ondivergence between human and mouse CD39. The chimeras were expressed inCHO cells and the ability of anti-human CD39 antibodies to bind thechimeras tested via FACS, as described in FIG. 14E. Table 2. Positivebinding was scored as “Yes” and lack of binding was scored as “No” andexamples of FACS plots used to generate this table are in FIGS. 14.F and14.G.

Specific residues critical for antibody contact can distinguishinhibitory antibodies 31414, 31418, and 31895 from 31901, 31905, and31873. Individual amino acids in the mouse sequence of human-mouseChimera #2, when reverted back to the respective human residue(resulting in Chimera #9,10), restore the ability of antibodies 31895,31414, 31418 to bind to CD39 but not the ability of 31901, 31905, or31873 to bind CD39. Mutation of individual residues in the context ofotherwise fully human CD39 (Chimeras #11,12) did not impair the bindingability of any of the tested antibodies. Co-mutation of two humanresidues to the cognate mouse residues (Chimeras #13,14) did not impairbinding by antibodies 31414, 31418 or 31895. In stark contrast,antibodies 31901, 31905, and 31873 completely lost their ability to bindChimeras #13 and 14. The ability of indicated antibodies to bind a givenchimera was determined by FACS. In particular, FIG. 14F and FIG. 14Gshow representative FACS plots used to populate this table and FIG. 14Gshows the importance of human CD39 residues N99, R154, and/or S153 inrecognition by antibodies represented by 31901, 31905, and 31873.

As demonstrated in FIG. 14E, Table 1, inhibitory antibodies 31414,31418, 31895, 31901, 31905 and 31873 can be distinguished from othermonoclonal anti-CD39 antibodies based on their inability to recognizeChimera #2. In Table 2, these antibodies are further distinguished bythe gain or loss of the ability to bind specific point mutants of hCD39or Chimera #2. Thus, these antibodies, while binding the same generalregion of human CD39, form distinct contacts with different criticalresidues in hCD39. Since these antibodies share the requirement forresidues E143-N158, they may share some common contact residues yet canbe differentiated based on the demonstrated unique points of contact.

(f) FACS Plots Highlighting the Importance of Human CD39 Residue D150and/or E153 in Recognition of Antibodies Represented by 31414, 31418,and 31895 and FACS Plots Highlighting the Importance of Human CD39Residues N99, R154, and/or E153 in Recognition by Antibodies Representedby 31901, 31905, and 31873

The methods are as provided above for the examples of inhibitoryantibodies that make distinct contacts with CD39.

The ability of indicated antibodies to bind to a given chimera wasdetermined by FACS.

While antibodies 31414, 31418, 31895, 31873, 31901, and 31905 all sharea common requirement for human CD39 residues E143-N158, these antibodiesmake different critical contacts with residues within and outside ofthis region. Thus, antibodies, which belong to the bin grouprepresented, by antibodies 27571, 27579, and 28347 (FIG. 14.D) can befurther distinguished into at least two more groups based on sensitivityto distinct residues. There are at least 5 bin groups: (1) Al-likeantibodies that compete each other for ECD binding yet do not inhibitECD activity, but do not compete with antibodies in bin groups 2,3,4, or5 for ECD binding and make critical contacts with N275-I277 as evidencedby loss of binding to Chimera #4; (2) 27536/28337-like antibodies thatcompete each other for ECD binding and can inhibit both ECD and cellularCD39 ATPase activity, but do not compete with antibodies in bin groups1,3,4 or 5 for ECD binding; (3) 27549-like antibodies that compete eachother for ECD binding and can inhibit CD39 ECD but not cellular CD39,and do not compete with antibodies in bin groups 1,2,4 or 5 for ECDbinding; (4) 31414/31418/31895-like antibodies that make criticalcontacts with E143-N158 in cellular CD39 including (but not limited to)D150 and E153, inhibit the ATPase activity of both ECD and cellularCD39, compete with each other for ECD binding, but do not compete withantibodies in bins 1, 2 or 3 for ECD binding; and (5)31873/31901/31905-like antibodies that make critical contacts withE143-N158 in cellular CD39 including (but not limited to) E153 and R154,as well as a sensitivity to residue N99, inhibit the ATPase activity ofboth ECD and cellular CD39, compete with each other for ECD binding, butdo not compete with antibodies in bins 1, 2, or 3 for ECD binding. Thus,there are anti-human CD39 antibodies that can be distinguished based ontheir affinity for ECD, affinity for cells, ability to inhibit ECDATPase activity, ability to inhibit cellular ATPase activity, and pointsof contact with CD39. For example, 27549 binds both ECD (FIG. 1) andcells well (FIG. 2) yet can only inhibit ECD ATPase activity. 27579binds ECD weakly but is a potent cellular CD39 inhibitor.

Example 16: Anti-CD39 Antibodies are Reversible Allosteric, notCompetitive, Inhibitors Due to V_(max) Suppression of V_(Max)

Anti-CD39 antibodies or isotype control antibody (100 nanomolar finalconcentration) were incubated with MEL-28 cells (35,000 MEL-28cells/well) endogenously expressing human CD39 at 37° C. for 20 minutesin the presence of EnzChek reagents (PNP & MESG). Immediately followingthe addition of ATP (final concentrations ranging from 0-450micromolar), the rate of ATP hydrolysis to free phosphate (Pi) by CD39was monitored over time at Abs360 nm using SpectraMax i3× plate reader.The initial enzyme velocity, ν0, was determined from the linear regionof Pi vs. time curve for each ATP concentration. The plot of ν0 vs.[ATP] was curve fit using non-linear regression of the Michaelis-Mentenkinetic model.

The ATP hydrolysis rate by CD39 expressed on MEL-28 cells can bemarkedly reduced by the anti-CD39 antibodies (see FIG. 15). The ATPhydrolysis rate in the presence of the anti-CD39 antibodies ranges from1.2 to 2.7 micromolar Pi per minute, which is much less than the ATPhydrolysis rate observed in the presence of an isotype control antibody(7.7 micromolar Pi per minute) and similar in magnitude to the panATPase inhibitor ARL (1.2 micromolar Pi per minute).

The plot of initial velocity versus ATP concentration for multipleconcentrations of the anti-CD39 antibody 29872 indicates that themechanism of inhibition of this IgG antibody is not competitive (seeFIG. 16 A.). The reduction in initial velocity is constant for ATPconcentrations above 100 micromolar (100, 200, 300 and 500 micromolar)in the presence of 5 nanomolar 29872. 29872 could be a non-competitiveinhibitor, an un-competitive inhibitor, or a mixed inhibitor of CD39(having properties of both non-competitive and un-competitiveinhibition). The monovalent Fab form of anti-CD39 antibody 29872 showeda very similar inhibition profile (see FIG. 16 B.), indicating that theCD39 inhibition activity of 29872 is not dependent on the bivalentstructure of the IgG and the potential properties that could result fromIgG bivalency such as CD39 crosslinking.

Many of the other anti-CD39 antibodies tested in this assay showed asimilar profile for CD39 enzymatic inhibition (data not shown),indicating that they also may be non-competitive inhibitors,un-competitive inhibitors, or mixed inhibitors of CD39. The mechanism ofenzymatic inhibition of these antibodies suggests that they retain theirfull inhibition of CD39 enzymatic inhibition at high ATP concentrations.The anti-CD39 antibodies appear to be reversible inhibitors.

Example 17: Anti-CD39 can Induce Internalization of CD39 on CynoMonocytes

Anti-CD39 antibodies were injected into cynomolgus monkeys to test forability to downregulate CD39 on cell surface of cyno monocytes. CD39internalization was assessed by FACS of whole blood samples collectedpre-dose, Day 1, Day 7, and Day 14 after antibody treatment.Non-competing anti-CD39-PE antibody (clone A1) was used to measure CD39levels on CD14+ gated monocytes. Data is shown as MFI of Al-PE on gatedcyno monocytes in FIG. 17.

Cynomolgus monkeys were injected with anti-CD39 antibodies at 10 mg/kg.Blood samples were collected prior to injection and on Day 1, Day 7, andDay 14 after treatment. For each time-point, 50 uL of cynomolgus wholeblood was incubated with 30 uL of staining buffer (PBS, 2% FBS, 2 mMEDTA, 3% mouse serum, 5% goat serum) containing CD14 and CD20 antibodies(eBioscience) and an Fc blocking reagent (BD) for 30 minutes at 4 C.CD39 antibody (clone eBioA1, eBioscience) was added to the sample andincubated for an additional 40 minutes at 4 degrees C. Followingincubation, the samples were treated with ACK lysis buffer(ThermoFisher) for 10 minutes at room temperature to lyse red bloodcells. Samples were washed several times with staining buffer and fixedwith 1% PFA (Sigma) before acquisition on a BD Fortessa X-20 flowcytometer. Total CD39 receptor expression on CD14 positive monocytes wasdetermined by mean fluorescence intensity.

CD39 was highly expressed on cyno monocytes prior to antibody treatmentin all blood samples tested (pre-dose). Anti-CD39 antibodies tested invivo had distinct internalization profiles where antibody 1 treatmentled to downregulation of CD39 on cell surface of monocytes and antibody2 had no effect on overall CD39 levels. Apparent decrease of CD39 levelsafter antibody 1 treatment was not due to A1 antibody competing withantibody 1 for binding to CD39 as the epitopes for A1 and antibody 1 aredistinct from each other.

Example 18: Anti-CD39 Antibody Increases Stimulated Human CD4⁺ and CD8⁺T Cell in the Presence of Exogenous ATP

Anti-CD3+anti-CD28 stimulated PBMCs were treated with anti-CD39 antibody31895 or isotype control in the presence of 50 μM ATP for 96 hours.Proliferation of CD4⁺ and CD8⁺ T cells was measured by Cell Trace Violetby flow cytometry.

FIG. 19 shows that anti-CD39 antibody increases proliferation ofstimulated human CD4⁺ and CD8⁺ T cell in the presence of exogenous ATP.The left side shows CD8⁺ T cells, with the x-axis showing antibody (nM)and the y-axis showing % CD8⁺ T cell proliferation. The right side showsCD4⁺ T cells, with the x-axis showing antibody (nM) and the y-axisshowing % CD4⁺ T cell proliferation. The inset to the right showssymbols for the respective antibodies and controls.

Example 19: Anti-CD39 Antibody Increase Stimulated PBMC Secretion ofINF-γ, TNF-α and IL-2

Human PBMCs were treated with anti-CD3+anti-CD28 and incubated withanti-CD39 antibody 31895 or isotype control in presence (B) or absence(A) of exogenous ATP (50 μM). Supernatants were harvested after 96 hoursand cytokines were measured using a Meso Scale Discovery human cytokinekit.

FIG. 20 shows anti-CD39 antibody 31895 increases cytokine secretion byanti-CD3+anti-CD28 activated PBMC in absence (A) or presence (B) ofexogenous ATP in a dose dependent manner. The top row shows results withexogenous ATP added and the bottom row shows results with no exogeonousATP added. The x-axis shows antibody (nM) and the y-axis shows secretionof INF-γ, TNF-α and IL-2, respectively.

Example 20: Anti-CD39 Antibody Increases Stimulated PBMC Secretion ofINF-γ, TNF-α, IL-2 and IL-1β

Human PBMCs were stimulated with anti-CD3+anti-CD28 and incubated withanti-CD39 antibodies 31895, HAO-391 (See, SEQ ID 10/SEQ ID 11 from WO2017/089334), HAO mAb4 (See SEQ ID 12/SEQ ID 13 from WO2017157948) orisotype control at a fixed concentration of 50 μg/ml in presence of ATP.Supernatants were harvested after 96 hours and analyzed by Meso ScaleDiscovery human cytokine kit.

FIG. 21 shows anti-CD39 antibody 31895 increased cytokine release byactivated PBMCs to a higher degree compared to anti-CD39 antibodiesHAO-391 (VL SEQ ID No. 10; VH SEQ ID No. 11 from WO 2017/089334) and HAOmAb4 (VL SEQ ID No. 12; VH SEQ ID No. 13 from WO2017157948). The x-axisindicates the antibody and/or conditions and the y-axis shows INF-γ,TNF-α, IL-2 and IL-1β, respectively.

Example 21: Anti-39 Antibody 31895 Increase Extracellular ATPAccumulation and Reduces Adenosine Generation by CD39⁺CD73⁺ SK-MEL-28Cells

SK-MEL-28 cells were treated with 31895, isotype control, or smallmolecule inhibitors (EHNA, ARL, or POM-1) for 1 hour and 50 μM ATP wasadded for 15 min prior to harvesting of the supernatants. Thesupernatants were analyzed for ATP levels using AmpGlo Kit (A) and foradenosine levels using LC/MS analysis (B). % Adenosine levels werenormalized to isotype control (100%) and SK-MEL-28 CD39 KO cells (0%).

The results are shown in FIG. 22. The left graph shows ATP accumulationand the right graph shows adenosine generation (LC/MC). The x-axis foreach graph shows conditions. The y-axis for the left graph shows ATP(μM) and the y-axis for the right graph shows % of adenosine levels.

Example S: Sequences

Table S provides sequences referred to herein.

TABLE S Sequences. SEQ ID NO: Region Scheme/Clone Sequence 1 CDR-H1Chothia GYTFTSY 2 CDR-H1 Chothia GYTFKSY 3 CDR-H1 Chothia GYIFKSY 4CDR-H1 Chothia GYTFQSY 5 CDR-H1 Chothia GYTFFSY 6 CDR-H1 Chothia GYTFVSY7 CDR-H1 Chothia GGTFSSLAIS 8 CDR-H1 Chothia GGTFSKLAIS 9 CDR-H1 ChothiaGGTFSHT 10 CDR-H1 Chothia GGTFSSL 11 CDR-H1 Chothia GGTFSLL 12 CDR-H1Chothia GGTFQSL 13 CDR-H1 Chothia GGTFPSN 14 CDR-H1 Chothia GGTFSAM 15CDR-H1 Chothia GGTFASL 16 CDR-H1 Chothia GGTFSWL 17 CDR-H1 ChothiaGGTFSSY 18 CDR-H1 Chothia GGTFGSY 19 CDR-H1 Chothia GGTFSKY 20 CDR-H1Chothia GGTFGRY 21 CDR-H1 Chothia GGTFESY 22 CDR-H1 Chothia GGTFSNY 23CDR-H1 Chothia GGAFSSY 24 CDR-H1 Chothia GFTFSSY 25 CDR-H1 Kabat SYYMH26 CDR-H1 Kabat SYEMH 27 CDR-H1 Kabat SYQMH 28 CDR-H1 Kabat SYYMY 29CDR-H1 Kabat SYFMH 30 CDR-H1 Kabat SLAIS 31 CDR-H1 Kabat KLAIS 32 CDR-H1Kabat HTAIS 33 CDR-H1 Kabat SLPIS 34 CDR-H1 Kabat LLAIS 35 CDR-H1 KabatSNAIS 36 CDR-H1 Kabat AMAIS 37 CDR-H1 Kabat WLAIS 38 CDR-H1 Kabat SYAIS39 CDR-H1 Kabat SYGIS 40 CDR-H1 Kabat KYGIS 41 CDR-H1 Kabat NYAIS 42CDR-H1 Kabat SYATS 43 CDR-H1 Kabat SYAIG 44 CDR-H1 Kabat SYSMN 45 CDR-H1Kabat SYGMN 46 CDR-H2 Chothia NPSGGST 47 CDR-H2 Chothia NPSVGS 48 CDR-H2Chothia NPSGGS 49 CDR-H2 Chothia NPLGGG 50 CDR-H2 Chothia NPRGGS 51CDR-H2 Chothia IPIFGT 52 CDR-H2 Chothia GFGT 53 CDR-H2 Chothia LPIGGT 54CDR-H2 Chothia LPIAGT 55 CDR-H2 Chothia LPIFGE 56 CDR-H2 Chothia IPRGGT57 CDR-H2 Chothia IPEFGI 58 CDR-H2 Chothia IPSIGT 59 CDR-H2 ChothiaIPISGT 60 CDR-H2 Chothia IPTFGT 61 CDR-H2 Chothia SSSSSY 62 CDR-H2Chothia WYDGSN 63 CDR-H2 Kabat VINPSGGSTSYAQKFQG 64 CDR-H2 KabatRINPSVGSTWYAQKFQG 65 CDR-H2 Kabat RINPSGGSTWYAQKFQG 66 CDR-H2 KabatKINPSGGSTWYAQKFQG 67 CDR-H2 Kabat VINPLGGGTSYAQKFQG 68 CDR-H2 KabatSINPRGGSTSYAQKFQG 69 CDR-H2 Kabat GIIPIFGTANYAQKFQG 70 CDR-H2 KabatGI--GFGTANYAQKFQG 71 CDR-H2 Kabat GILPIGGTANYAQKFQG 72 CDR-H2 KabatGILPIAGTANYAQKFQG 73 CDR-H2 Kabat GILPIFGEANYAQKFQG 74 CDR-H2 KabatGIIPRGGTANYAQKFQG 75 CDR-H2 Kabat SIIPIFGTANYAQKFRG 76 CDR-H2 KabatSIIPEFGIANYAQKFQG 77 CDR-H2 Kabat SIIPIFGTANYAQKFQG 78 CDR-H2 KabatGIIPISGTANYAQEFQG 79 CDR-H2 Kabat GIIPTFGTANYAQKFQG 80 CDR-H2 KabatSISSSSSYIYYADSVKG 81 CDR-H2 Kabat VIWYDGSNKYYADSVKG 82 CDR-H3GKREGGTEYLRH 83 CDR-H3 GKREGGTEYLRK 84 CDR-H3 GKREGGTEYLRS 85 CDR-H3GKREGGTEYLRN 86 CDR-H3 GKREGGTEYLRV 87 CDR-H3 GGAKYASTYGMDV 88 CDR-H3GGAKYASTHGMDV 89 CDR-H3 GGAKYASQLGMDV 90 CDR-H3 GGAKYASKWGMDV 91 CDR-H3GGAKYAVGYGMDV 92 CDR-H3 GGAKYAGRYGMDV 93 CDR-H3 GGAKYARTYGMDV 94 CDR-H3ESGGYRDHRLDV 95 CDR-H3 ESGTYRDHRLDV 96 CDR-H3 ESGGYRDHRLGV 97 CDR-H3DFTDYSSGYSSGWTY 98 CDR-H3 DTLYSSGAYYGYNV 99 CDR-H3 AKRGYDSYGGVYFDY 100CDR-H3 GPTVTATTSIGTHNWFDP 101 CDR-H3 EGRGYDSSRYYKFWFDPWGQGTLVTVSS 102CDR-H3 DGGGYRHHYFDL 103 CDR-H3 ESGGYRDHKLDV 104 CDR-H3 DGGGYQHHYFDL 105CDR-H3 DSGYHRHYSDY 106 CDR-H3 DPLGIRKHWFDP 107 CDR-H3 DTPRWRYHYFDY 108CDR-H3 ERRGSLALGMDV 109 CDR-H3 DLGGYSYGEPYYYYYGMDV 110 CDR-L1RASQSVSSSYLA 111 CDR-L1 RASQSVASSYLA 112 CDR-L1 EASQSVSYSYLA 113 CDR-L1KASESVSSSYLA 114 CDR-L1 RASQYVSSSYLA 115 CDR-L1 KSSQSVLFSSNNKNYLA 116CDR-L1 KSSRSVLFSSNNKNYLA 117 CDR-L1 KSSKSVLYSNNNKNYLA 118 CDR-L1RASQSVGSNLA 119 CDR-L1 KSSQSVLYSSNNKNYLA 120 CDR-L1 QASQDISNYLN 121CDR-L1 RASQSVSSYLA 122 CDR-L1 RASQSVSRYLA 123 CDR-L1 RASQSISSWLA 124CDR-L1 RASQSVSSDYLA 125 CDR-L2 GASSRAT 126 CDR-L2 GASNRHT 127 CDR-L2YASSRAY 128 CDR-L2 GASSRAN 129 CDR-L2 YASSRAT 130 CDR-L2 YASNRAT 131CDR-L2 WASTRES 132 CDR-L2 WASSRES 133 CDR-L2 WASTRQS 134 CDR-L2 WASTRAS135 CDR-L2 GASTRAT 136 CDR-L2 GASTRAS 137 CDR-L2 DASNLET 138 CDR-L2DASNRAT 139 CDR-L2 DASKRAT 140 CDR-L2 KASSLES 141 CDR-L3 QQYHSYIT 142CDR-L3 QQYHNAIT 143 CDR-L3 QQYYFYIT 144 CDR-L3 QQYHSALT 145 CDR-L3QQYHGGIT 146 CDR-L3 QQYHRRIT 147 CDR-L3 QQYHSGIT 148 CDR-L3 QQYYLYPLT149 CDR-L3 QQYWTYPLT 150 CDR-L3 QQYLLYPLT 151 CDR-L3 QQYLIWPLT 152CDR-L3 QQYLLWPLT 153 CDR-L3 QQFYFFPPT 154 CDR-L3 QQAYTFPPT 155 CDR-L3QQYYIFPPT 156 CDR-L3 QQRNFYPPT 157 CDR-L3 QQFVLWPRT 158 CDR-L3 QQHVNFPLT159 CDR-L3 QQSVFWPIT 160 CDR-L3 QQLTKWPLT 161 CDR-L3 QQDVLWPLT 162CDR-L3 QQYGLFPIT 163 CDR-L3 QQHTVWPIT 164 CDR-L3 QQVLNYPLT 165 CDR-L3QQSYFLPPT 166 CDR-L3 QQAHSSPYT 167 Leader for LeaderMKYLLPTAAAGLLLLAAQPAMA scFV, scFv-Fc 168 Linker for LinkerGGGGSGGGGSGGGGS scFV, scFV-FC 169 C-Term Tag for C-Term Tag GPGGQHHHHHHscFV, scFV-FC 170 C-Term Tag for C-Term TagPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD scFv, scFV-FCTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 171scFv 29872 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKEPGASVKVSCKAPGYTFTSYYMHWVRQAPGQG LEWMGVINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRH WGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK PGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFGGGTKVEI KGPGGQHHHHHH 172 scFv 31895MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEV KKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTS TVYMELSSLRSEDTAVYYCARGKREGGTEYLRKWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQS PGTLSLSPGERATLSCRASQSVASSYLAWYQQKPGQAPRLLIYGASNRHTGIPDRFSGSGSGTDFT LTISRLEPEDFAVYYCQQYHNAITFGGGTKVEIKGPGGQHHHHHH 173 scFv 31414 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQG LEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRN WGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK PGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFGGGTKVEI KGPGGQHHHHHH 174 scFv 31905MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEV KKPGSSVKVSCKASGGTFPSNAISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRVTITADESTSTA YMELSSLRSEDTAVYYCARGGAKYARTYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSP DSLAVSLGERATINCKSSKSVLYSNNNKNYLAWYQQKPGQPPKLLIYWASTRQSGVPDRFSGSGSG TDFTLTISSLQAEDVAVYYCQQYLLYPLTFGGGTKVEIKGPGGQHHHHHH 175 scFv-Fc 29872 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKEPGASVKVSCKAPGYTFTSYYMHWVRQAPGQG LEWMGVINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRH WGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK PGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFGGGTKVEI KPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K176 scFv-Fc 31895 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQG LEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRK WGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVASSYLAWYQQK PGQAPRLLIYGASNRHTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHNAITFGGGTKVEI KPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K177 scFv-Fc 31414 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQG LEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRN WGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQK PGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFGGGTKVEI KPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K178 scFv-Fc 31905 MKYLLPTAAAGLLLLAAQPAMAQVQLVQSGAEVKKPGSSVKVSCKASGGTFPSNAISWVRQAPGQG LEWMGGIGFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYARTYGMDVW GQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSKSVLYSNNNKNYLAW YQQKPGQPPKLLIYWASTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLLYPLTFGGG TKVEIKPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 179 VH 27579 QVQLVQSGAEVKEPGASVKVSCKAPGYTFTSYYMHWVRQAPGQGLEWMGVINPSGGSTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 180 VH 31895 QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRKWGQGTLVTVSS 181 VH 31415 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYQMHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRSWGQGTLVTVSS 182 VH 31414 QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRNWGQGTLVTVSS 183 VH 31891 QVQLVQSGAEVKKPGASVKVSCKASGYIFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRVWGQGTLVTVSS 184 VH 29871 QVQLVQSGAEVKKPGASVKVSCKASGYTFQSYYMHWVRQAPGQGLEWMGKINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 185 VH 31418 QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 186 VH 31431 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYQMHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 187 VH 31421 QVQLVQSGAEVKKPGASVKVSCKASGYTFFSYYMYWVRQAPGQGLEWMGVINPLGGGTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 188 VH 31429 QVQLVQSGAEVKKPGASVKVSCKASGYTFVSYFMHWVRQAPGQGLEWMGSINPRGGSTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 189 VH 29872 QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSS 190 VH 28347 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSLAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTNTAYMELSSLRSEDTAVYYCARGGAKYASTYGMDVWGQGTTVTVSS 191 VH 31896 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSKLAISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESASTAYMELSSLRSEDTAVYYCARGGAKYASTHGMDVWGQGTTVTVSS 192 VH 31432 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSHTAISWVRQAPGQGLEWMGGILPIGGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASQLGMDVWGQGTTVTVSS 193 VH 31915 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSLPISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASKWGMDVWGQGTTVTVSS 194 VH 31436 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSLLAISWVRQAPGQGLEWMGGILPIAGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYAVGYGMDVWGQGTTVTVSS 195 VH 31437 QVQLVQSGAEVKKPGASVKVSCKASGGTFQSLAISWVRQAPGQGLEWMGGILPIGGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYAGRYGMDVWGQGTTVTVSS 196 VH 31905 QVQLVQSGAEVKKPGSSVKVSCKASGGTFPSNAISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCARGGAKYARTYGMDVWGQGTTVTVSS 197 VH 31901 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSLPISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCARGGAKYAGRYGMDVWGQGTTVTVSS 198 VH 29852 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAMAISWVRQAPGQGLEWMGGILPIAGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASTYGMDVWGQGTTVTVSS 199 VH 29851 QVQLVQSGAEVKKPGSSVKVSCKASGGTFASLAISWVRQAPGQGLEWMGGILPIFGEANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASTYGMDVWGQGTTVTVSS 200 VH 29857 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSWLAISWVRQAPGQGLEWMGGIIPRGGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASTYGMDVWGQGTTVTVSS 201 VH 27571 QVQLVQSGAEVKKPGSSVKASCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFRG RVTITADESTSTTYMELSSLRSEDTAVYYCARESGGYRDHRLDVWGQGTMVTVSS 202 VH 31861 QVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYGISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARESGTYRDHRLDVWGQGTMVTVSS 203 VH 31873 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSKYGISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARESGGYRDHRLGVWGQGTMVTVSS 204 VH 31393 QVQLVQSGAEVKKPGSSVKVSCKASGGTFESYGISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQG RVTITADESTSTTYMELSSLRSEDTAVYYCARESGGYRDHRLDVWGQGTMVTVSS 205 VH 27534 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDFTDYSSGYSSGWTYWGQGTLVTVSS 206 VH 27536 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDTLYSSGAYYGYNVWGQGTMVTVSS 207 VH 27588 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARAKRGYDSYGGVYFDYWGQGTLVTVSS 208 VH 27590 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARGPTVTATTSIGTHNWFDPWGQGTLVTVSS 209 VH 27597QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARE GRGYDSSRYYKFWFDPWGQGTLVTVSS 210 VH27575 QVQLVQSGAEVKEPGSSVKVSCKASGGTFSSYATSWVRQAPGQGLEWMGGIIPISGTANYAQEFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDGGGYRHHYFDLWGRGTLVTVSS 211 VH 27568 QVQLVQSGAEVKKPGSSVKVPCKASGGTFSSYAISWVRQAPEQGLEWMGSIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAGESGGYRDHKLDVWGQGTVVTVSS 212 VH 27577 QVQLVQSGAEVKKPGSSVKVSCKASGGAFSSYAIGWVRQAPGQGLEWMGGIIPTFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDGGGYQHHYFDLWGRGTLVTVSS 213 VH 27587 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARESGGYRDHKLDVWGQGTMVTVSS 214 VH 27589 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDSGYHRHYSDYWGQGTLVTVSS 215 VH 27596 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDPLGIRKHWFDPWGQGTLVTVSS 216 VH 27535 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDTPRWRYHYFDYWGQGTLVTVSS 217 VH 27550 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARERRGSLALGMDVWGQGTLVTVSS 218 VH 27549 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMNWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLGGYSYGEPYYYYYGMDVWGQGTTVTVSS 219 VL 27579EIVLTQSPGTLSLSPGERATLSCRASQSVSSSY LAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFG GGTKVEIK 220 VL 31895EIVLTQSPGTLSLSPGERATLSCRASQSVASSY LAWYQQKPGQAPRLLIYGASNRHTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHNAITFG GGTKVEIK 221 VL 31891EIVLTQSPGTLSLSPGERATLSCRASQSVSSSY LAWYQQKPGQAPRLLIYYASSRAYGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHNAITFG GGTKVEIK 222 VL 31418EIVLTQSPGTLSLSPGERATLSCRASQSVSSSY LAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYYFYITFG GGTKVEIK 223 VL 31430EIVLTQSPGTLSLSPGERATLSCEASQSVSYSY LAWYQQKPGQAPRLLIYGASSRANGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSALTFG GGTKVEIK 224 VL 31431EIVLTQSPGTLSLSPGERATLSCRASQSVASSY LAWYQQKPGQAPRLLIYGASNRHTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHGGITFG GGTKVEIK 225 VL 31421EIVLTQSPGTLSLSPGERATLSCKASESVSSSY LAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHRRITFG GGTKVEIK 226 VL 31429EIVLTQSPGTLSLSPGERATLSCRASQYVSSSY LAWYQQKPGQAPRLLIYYASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSGITFG GGTKVEIK 227 VL 28347DIVMTQSPDSLAVSLGERATINCKSSQSVLFSS NNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYL YPLTFGGGTKVEIK 228 VL 31896DIVMTQSPDSLAVSLGERATINCKSSRSVLFSS NNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYWT YPLTFGGGTKVEIK 229 VL 31915DIVMTQSPDSLAVSLGERATINCKSSQSVLFSS NNKNYLAWYQQKPGQPPKLLIYWASSRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYWT YPLTFGGGTKVEIK 230 VL 31905DIVMTQSPDSLAVSLGERATINCKSSKSVLYSN NNKNYLAWYQQKPGQPPKLLIYWASTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLL YPLTFGGGTKVEIK 231 VL 31901GIVMTQSPDSLAVSLGERATINCKSSQSVLFSS NNKNYLAWYQQKPGQPPKLLIYWASTRASGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYL YPLTFGGGTKVEIK 232 VL 27571EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYLIWPLTFG GGTKVEIK 233 VL 31861EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYLLWPLTFG GGTKVEIK 234 VL 31873EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRASGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYLLWPLTFG GGTKVEIK 235 VL 28337DIVMTQSPDSLAVSLGERATINCKSSQSVLFSS NNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQFYF YPPTFGGGTKVEIK 236 VL 27536DIVMTQSPDSLAVSLGERATINCKSSQSVLYSS NNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQAYT FPPTFGGGTKVEIK 237 VL 27588DIQMTQSPSSLSASVGDRVTITCQASQDISNYL NWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYYIFPPTFG GGTKVEIK 238 VL 27590EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNFYPPTFG GGTKVEIK 239 VL 27597EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQFVLWPRTFG GGTKVEIK 240 VL 27575EIVLTQSPATLSLSPGERATLSCRASQSVSRYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHVNFPLTFG GGTKVEIK 241 VL 27568EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSVFWPITFG GGTKVEIK 242 VL 27577EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQLTKWPLTFG GGTKVEIK 243 VL 27587EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQDVLWPLTFG GGTKVEIK 244 VL 27589DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYGLFPITFG GGTKVEIK 245 VL 27596EIVMTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHTVWPITFG GGTKVEIK 246 VL 27535EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQVLNYPLTFG GGTKVEIK 247 VL 27550DIQMTQSPSSLSASVGDRVTITCQASQDISNYL NWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQSYFLPPTFG GGTKVEIK 248 VL 27549EIVLTQSPGTLSLSPGERATLSCRASQSVSSDY LAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQAHSSPYTF GGGTKVEIK 249 hCD39MEDTKESNVKTFCSKNILAILGFSSIIAVIALL AVGLTQNKALPENVKYGIVLDAGSSHTSLYIYKWPAEKENDTGVVHQVEECRVKGPGISKFVQKVN EIGIYLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEELADRVLDVVERSLSNYPFDFQG ARIITGQEEGAYGWITINYLLGKFSQKTRWFSIVPYETNNQETFGALDLGGASTQVTFVPQNQTIE SPDNALQFRLYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLY KTPCTKRFEMTLPFQQFEIQGIGNYQQCHQSILELFNTSYCPYSQCAFNGIFLPPLQGDFGAFSAF YFVMKFLNLTSEKVSQEKVTEMMKKFCAQPWEEIKTSYAGVKEKYLSEYCFSGTYILSLLLQGYHF TADSWEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLSHSTYVFLMVLFSLVLFTVAIIG LLIFHKPSYFWKDMV 250 mCD39MEDIKDSKVKRFCSKNILIILGFTSILAVIALI AVGLTQNKPLPENVKYGIVLDAGSSHTNLYIYKWPAEKENDTGVVQQLEECQVKGPGISKYAQKTD EIGAYLAECMELSTELIPTSKHHQTPVYLGATAGMRLLRMESEQSADEVLAAVSTSLKSYPFDFQG AKIITGQEEGAYGWITINYLLGRFTQEQSWLSLISDSQKQETFGALDLGGASTQITFVPQNSTIES PENSLQFRLYGEDYTVYTHSFLCYGKDQALWQKLAKDIQVSSGGVLKDPCFNPGYEKVVNVSELYG TPCTKRFEKKLPFDQFRIQGTGDYEQCHQSILELFNNSHCPYSQCAFNGVFLPPLHGSFGAFSAFY FVMDFFKKVAKNSVISQEKMTEITKNFCSKSWEETKTSYPSVKEKYLSEYCFSGAYILSLLQGYNF TDSSWEQIHFMGKIKDSNAGWTLGYMLNLTNMIPAEQPLSPPLPHSTYIGLMVLFSLLLVAVAITG LFIYSKPSYFWKEAV 251 MacacaMLFDSILSTVGLSKLVSVVSSPAAALSKSNVKT fascicularisFCSKNILAILGESSIIAVIALLAVGLTQNKALP cCD39ENIKYGIVLDAGSSHTSLYIYKWPAEKENDTGV VHQVEECRVKGPGISKYVQKVNEIGIYLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEE LADRVLDVVERSLSNYPFDFQGARIITGQEEGAYGWITINYLLGKFSQKTRWFSIVPYETNNQETF GALDLGGASTQITFVPQNQTTESPDNALQFRLYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASN EILRDPCFHPGYKKVVNVSDLYKTPCTKRFEMTLPFQQFEIQGIGNYQQCHQSVLELFNTSYCPYS QCAFNGIFLPPLQGDFGAFSAFYFVMNFLNLTSEKVSQEKVTEMMKKFCSQPWEEIKTSYAGVKEK YLSEYCFSGTYILSLLLQGYHFTADSWEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLS HSTYVFLMVLFSLVLVIVAIIGLLIFHKPSYFW KDMV252 hCD39ECD TQNKALPENVKYGIVLDAGSSHTSLYIYKWPAEKENDTGVVHQVEECRVKGPGISKFVQKVNEIGI YLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEELADRVLDVVERSLSNYPFDFQGARII TGQEEGAYGWITINYLLGKFSQKTRWFSIVPYETNNQETFGALDLGGASTQVTFVPQNQTIESPDN ALQFRLYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLYKTPC TKRFEMTLPFQQFEIQGIGNYQQCHQSILELFNTSYCPYSQCAFNGIFLPPLQGDFGAFSAFYFVM KFLNLTSEKVSQEKVTEMMKKFCAQPWEEIKTSYAGVKEKYLSEYCFSGTYILSLLLQGYHFTADS WEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLSHSTYVFLMVLFSLVLFTVAIIGLLIF HKPSYFWKDMV 253 mCD39ECDTQNKPLPENVKYGIVLDAGSSHTNLYIYKWPAE KENDTGVVQQLEECQVKGPGISKYAQKTDEIGAYLAECMELSTELIPTSKHHQTPVYLGATAGMRL LRMESEQSADEVLAAVSTSLKSYPFDFQGAKIITGQEEGAYGWITINYLLGRFTQEQSWLSLISDS QKQETFGALDLGGASTQITFVPQNSTIESPENSLQFRLYGEDYTVYTHSFLCYGKDQALWQKLAKD IQVSSGGVLKDPCFNPGYEKVVNVSELYGTPCTKRFEKKLPFDQFRIQGTGDYEQCHQSILELFNN SHCPYSQCAFNGVFLPPLHGSFGAFSAFYFVMDFFKKVAKNSVISQEKMTEITKNFCSKSWEETKT SYPSVKEKYLSEYCFSGAYILSLLQGYNFTDSSWEQIHFMGKIKDSNAGWTLGYMLNLTNMIPAEQ PLSPPLPHSTYIGLMVLFSLLLVAVAITGLFIYSKPSYFWKEAV 254 cCD39ECD TQNKALPENIKYGIVLDAGSSHTSLYIYKWPAEKENDTGVVHQVEECRVKGPGISKYVQKVNEIGI YLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEELADRVLDVVERSLSNYPFDFQGARII TGQEEGAYGWITINYLLGKFSQKTRWFSIVPYETNNQETFGALDLGGASTQITFVPQNQTTESPDN ALQFRLYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLYKTPC TKRFEMTLPFQQFEIQGIGNYQQCHQSVLELFNTSYCPYSQCAFNGIFLPPLQGDFGAFSAFYFVM NFLNLTSEKVSQEKVTEMMKKFCSQPWEEIKTSYAGVKEKYLSEYCFSGTYILSLLLQGYHFTADS WEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLSHSTYVFLMVLFSLVLVIVAIIGLLIF HKPSYFWKDMV 255 HC 31895QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYE MHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARG KREGGTEYLRKWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 256 LC 31895EIVLTQSPGTLSLSPGERATLSCRASQSVASSY LAWYQQKPGQAPRLLIYGASNRHTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHNAITFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 257 HC 31415 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYQMHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRSWGQGTLVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVMHEALHNHYTQKSLSLSLGK 258 LC 31415 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTISRLEPEDFAVYYCQQYHSYITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 259 HC 31891QVQLVQSGAEVKKPGASVKVSCKASGYIFKSYE MHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARG KREGGTEYLRVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 260 LC 31891EIVLTQSPGTLSLSPGERATLSCRASQSVSSSY LAWYQQKPGQAPRLLIYYASSRAYGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHNAITFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 261 HC 31418 QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYEMHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGKREGGTEYLRHWGQGTLVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVMHEALHNHYTQKSLSLSLGK 262 LC 31418 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTISRLEPEDFAVYYCQQYYFYITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 263 HC 31430QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYE MHWVRQAPGQGLEWMGRINPSGGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARG KREGGTEYLRHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 264 LC 31430EIVLTQSPGTLSLSPGERATLSCEASQSVSYSY LAWYQQKPGQAPRLLIYGASSRANGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSALTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 265 HC 31915 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSLPISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCARGGAKYASKWGMDVWGQGTTVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 266 LC 31915 DIVMTQSPDSLAVSLGERATINCKSSQSVLFSSNNKNYLAWYQQKPGQPPKLLIYWASSRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYWTYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC 267 HC 31905QVQLVQSGAEVKKPGSSVKVSCKASGGTFPSNA ISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGA KYARTYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGK 268 LC 31905DIVMTQSPDSLAVSLGERATINCKSSKSVLYSN NNKNYLAWYQQKPGQPPKLLIYWASTRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLL YPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 269 HC 31901 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSLPISWVRQAPGQGLEWMGGIGFGTANYAQKFQGRV TITADESTSTAYMELSSLRSEDTAVYYCARGGAKYAGRYGMDVWGQGTTVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 270 LC 31901 GIVMTQSPDSLAVSLGERATINCKSSQSVLFSSNNKNYLAWYQQKPGQPPKLLIYWASTRASGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC 271 HC 31861QVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYG ISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARE SGTYRDHRLDVWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 272 LC 31861EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYLLWPLTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 273 HC 31873 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSKYGISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARESGGYRDHRLGVWGQGTMVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 274 LC 31873 EIVMTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQAPRLLIYGASTRASGIPARFSGSG SGTEFTLTISSLQSEDFAVYYCQQYLLWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 275 HC 31393QVQLVQSGAEVKKPGSSVKVSCKASGGTFESYG ISWVRQAPGQGLEWMGSIIPEFGIANYAQKFQGRVTITADESTSTTYMELSSLRSEDTAVYYCARE SGGYRDHRLDVWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK 276 LC 31393EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYLLWPLTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 277 HC 27597 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAREGRGYDSSRYYKFWFDPWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 278 LC 27597 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQFVLWPRTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 279 HC 27575QVQLVQSGAEVKEPGSSVKVSCKASGGTFSSYA TSWVRQAPGQGLEWMGGIIPISGTANYAQEFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARD GGGYRHHYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 280 LC 27575EIVLTQSPATLSLSPGERATLSCRASQSVSRYL AWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQHVNFPLTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 281 HC 27568 QVQLVQSGAEVKKPGSSVKVPCKASGGTFSSYAISWVRQAPEQGLEWMGSIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAGESGGYRDHKLDVWGQGTVVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVMHEALHNHYTQKSLSLSLGK 282 LC 27568 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQSVFWPITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 283 HC 27577QVQLVQSGAEVKKPGSSVKVSCKASGGAFSSYA IGWVRQAPGQGLEWMGGIIPTFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARD GGGYQHHYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK 284 LC 27577EIVMTQSPATLSVSPGERATLSCRASQSVGSNL AWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQLTKWPLTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 285 HC 27587 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARESGGYRDHKLDVWGQGTMVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 286 LC 27587 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQDVLWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 287 HC 27589QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARD SGYHRHYSDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGK 288 LC 27589DIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYGLFPITFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 289 HC 27596 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARDPLGIRKHWFDPWGQGTLVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVMHEALHNHYTQKSLSLSLGK 290 LC 27596 EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQHTVWPITFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 291 HC 27535QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYA ISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARD TPRWRYHYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVM HEALHNHYTQKSLSLSLGK 292 LC 27535EIVLTQSPATLSLSPGERATLSCRASQSVSSYL AWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQVLNYPLTFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 293 HC 27550 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARERRGSLALGMDVWGQGTLVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVESCSVMHEALHNHYTQKSLSLSLGK 294 LC 27550 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSG SGTDFTFTISSLQPEDIATYYCQQSYFLPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC 295 HC 27549QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYG MNWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD LGGYSYGEPYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK 296 LC27549 EIVLTQSPGTLSLSPGERATLSCRASQSVSSDYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTISRLEPEDFAVYYCQQAHSSPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC 297 HC 31414QVQLVQSGAEVKKPGASVKVSCKASGYTFKSYE MHWVRQAPGQGLEWMGRINPSVGSTWYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARG KREGGTEYLRNWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK 298 LC 31414EIVLTQSPGTLSLSPGERATLSCRASQSVSSSY LAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYHSYITFG GGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

EQUIVALENTS

The disclosure set forth above may encompass multiple distinctinventions with independent utility. Although each of these inventionshas been disclosed in its preferred form(s), the specific embodimentsthereof as disclosed and illustrated herein are not to be considered ina limiting sense, because numerous variations are possible. The subjectmatter of the inventions includes all novel and nonobvious combinationsand subcombinations of the various elements, features, functions, and/orproperties disclosed herein. The following claims particularly point outcertain combinations and subcombinations regarded as novel andnonobvious. Inventions embodied in other combinations andsubcombinations of features, functions, elements, and/or properties maybe claimed in this application, in applications claiming priority fromthis application, or in related applications. Such claims, whetherdirected to a different invention or to the same invention, and whetherbroader, narrower, equal, or different in scope in comparison to theoriginal claims, also are regarded as included within the subject matterof the inventions of the present disclosure.

What is claimed is:
 1. An antigen binding protein that bindsspecifically to a human CD39 (hCD39) and is capable of 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of the following: a)inhibiting binding of CD39 to ATP; b) inhibiting conversion by CD39 ofATP to ADP and/or ADP to AMP; c) decreasing affinity of CD39 for ATP orADP; d) inhibiting or impeding release of ADP or AMP from CD39; e)impeding or inhibiting CD39 processivity; f) inhibiting plateletaggregation; g) decreasing levels of phosphate, ADP, AMP, and/oradenosine and/or increasing levels of ATP; h) increasing T effector cellfunction; i) decreasing the number of regulatory T cells in tissues orin circulation; j) suppressing regulatory T cells or regulatory T cellactivity; k) increasing B cell function; l) increasing antigenpresenting cell function; m) inhibiting CD39 function on tumor cells; n)inhibiting processing of at least one of phospho-antigen fromphosphorylated isoprenoid, phosphorylated vitamin B metabolite, and/orphosphorylated riboflavin; o) decreasing or preventing activation ofphospho antigen specific T cells selected from MAIT cells and γδ Tcells; p) inhibiting angiogenesis; q) increasing proliferation ofstimulated CD4⁺ and CD8⁺ T cells; r) increasing stimulated PBMCSecretion of INF-γ, TNF-α, IL-2 and/or IL-1β.
 2. The antigen bindingprotein of claim 1, wherein the antigen binding protein has 1, 2, 3, 4,5, 6, or 7 of the following characteristics: a) is a monoclonalantibody; b) is a human antibody, a humanized antibody, or a chimericantibody; c) is a bispecific antibody, a multi-specific antibody, adiabody, or a multivalent antibody; d) is of the IgG1, IgG2, IgG3, IgG4,or IgM type; e) is an antigen-binding antibody fragment; f) is a Fabfragment, a Fab′ fragment, a F(ab′)2 fragment, or an Fv fragment; and/org) is a single chain antibody, a single domain antibody, or a nanobody.3. A pharmaceutical composition comprising an effective amount of anantibody which binds to hCD39 and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, or 16 of the following of characteristics: a) blocks ordecreases hydrolysis of ATP to ADP and/or ADP to AMP as determined by atleast one of: (i) a decreased phosphate release (Pi), (ii) an increasein ATP levels, and (iii) a decrease of ADP, AMP, and/or adenosinelevels, b) increases T effector cell activity; c) suppresses regulatoryT cell or decreases a regulatory T cell activity; d) decreases number ofregulatory T cells in tissues or in circulation; e) increases B cellfunction; f) increases antigen presenting cell function; g) inhibitsCD39 function on tumor cells; h) blocks or inhibits processing of atleast one of phospho-antigen from a phosphorylated isoprenoid,phosphorylated vitamin B metabolite, and phosphorylated riboflavin; i)decreases or prevents activation of phospho antigen specific T cellsselected from MAIT cells and γβ T cells; k) inhibits angiogenesis; l)decreases affinity for ATP and/or ADP; m) inhibits release of ADP or AMPfrom CD39; n) impedes or inhibits CD39 processivity; o) inhibitsplatelet aggregation; p) increases proliferation of stimulated CD4⁺ andCD8⁺ T cells; r) increases stimulated PBMC Secretion of INF-γ, TNF-α,IL-2, and/or IL-1β.
 4. A pharmaceutical composition comprising theantigen-binding protein of claim 1 or claim
 2. 5. The pharmaceuticalcomposition of claim 4, further comprising an effective amount of atleast one of the following a) an anti-PD-1 antibody, b) an anti-PD-L1antibody, c) an anti-CD73 antibody, d) an anti-CD38 antibody, e) ananti-A2A receptor antibody, f) an anti-A2B receptor antibody, g) ananti-A2A/A2B dual receptor antibody, or any combination thereof, or h) asmall molecule inhibitor, or a combination thereof.
 6. Thepharmaceutical composition of claim 4 or claim 5, further comprising oneor both of a) an antibody to an inhibitory receptor or ligand and/or b)an antibody to a costimulatory receptor or ligand, or a combinationthereof.
 7. The pharmaceutical composition of claim 6, wherein (i) theinhibitory receptor or ligand is at least one of CTLA-4, PD-L2, LAG-3,Tim3, neuritin, BTLA, CECAM-1, CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-R,HHLA2, ILT2, ILT3, ILT4, HLA-G, HLA-C, and/or a Killer-cellimmunoglobulin-like receptor (KIR) and/or (ii) the costimulatoryreceptor or ligand is at least one of OX40, CD2, CD27, CDS, ICAM-1,LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM,CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and/or CD83.
 8. Thepharmaceutical composition of claim 7, wherein the costimulatoryreceptor or ligand LFA-1 further comprises an LFA-1 β-chain CD18 and/oran LFA-1 α-chain CD11a.
 9. The antigen binding protein of claim 1,wherein the antigen binding protein has one or more of the followingcharacteristics: a) binds to a human CD39 polypeptide or a variantthereof with a KD of less than about 20 nM; b) binds to a cyno CD39polypeptide or a variant thereof with a KD of less than about 200 nM; c)binds to a murine CD39 polypeptide or a variant thereof with a KD ofless than about 200 nM; or d) a combination of at least 2 of a), b), andc).
 10. An antigen binding protein that competes or is capable ofcompeting for binding to human CD39 with a reference antigen bindingprotein, wherein the reference antigen binding protein is the antigenbinding protein of claim
 1. 11. An antigen binding protein that binds toor is capable of competing for binding to human CD39 with a referenceantigen binding protein, wherein the reference antigen binding proteinbinds to an epitope at positions 143-158 or 274-277 of SEQ ID NO: 249 ona human CD39 polypeptide, including, but not limited to, D150, E153,R154 or N99 alone or in combination with D150, E153, R154 or anycombination thereof.
 12. The antigen binding protein of claim 10 orclaim 11, wherein the antigen binding protein and the reference antibodycross-compete or are capable of cross-competing for binding to a humanCD39.
 13. The antigen binding protein of claim 1, comprising a humanheavy chain constant region or fragment or a variant thereof, whereinthe constant region variant comprises up to 20 conservatively modifiedamino acid substitutions from any sequence set forth SEQ ID NOs:179-218.
 14. An isolated antibody molecule capable of binding to humanCD39 (hCD39), comprising a heavy chain variable region (VH) and a lightchain variable region (VL), VH and/or VL comprising 1, 2, 3, 4, 5, or 6of: a) a VHCDR1 having the sequence set forth in SEQ ID NOs: 1-45, b) aVHCDR2 having the sequence set forth in SEQ ID NOs: 46-81, c) a VHCDR3having the sequence set forth in SEQ ID NOs: 82-109, d) a VLCDR1 havingthe sequence set forth in SEQ ID NOs: 110-124, e) a VLCDR2 having thesequence set forth in SEQ ID NOs: 125-140, and f) a VLCDR3 having thesequence set forth in SEQ ID NOs: 141-166.
 15. An isolated antibodymolecule capable of binding to human CD39 (hCD39), comprising a heavychain variable region (VH) and a light chain variable region (VL), theVH comprising, a) a VHCDR1 having a sequence set forth in SEQ ID NOs:1-45, b) a VHCDR2 having a sequence set forth in SEQ ID NOs: 46-81, andc) a VHCDR3 having a sequence set forth in SEQ ID NOs: 82-109; and theVL comprising, a) a VLCDR1 having a sequence set forth in SEQ ID NO:110-124, b) a VLCDR2 having a sequence set forth in SEQ ID NO: 125-140,and c) a VLCDR3 having a sequence set forth in SEQ ID NO: 141-166. 16.An isolated nucleic acid encoding an antigen binding protein accordingto claim 1, claim 14, or claim
 15. 17. An expression vector comprisingthe nucleic acid according to claim
 16. 18. A prokaryotic or eukaryotichost cell comprising the vector of claim
 17. 19. An oncolytic virusencoding the nucleic acid of either of claim 16 or
 17. 20. A method forthe production of a recombinant protein comprising the steps ofexpressing a nucleic acid according to claim 16 in a prokaryotic oreukaryotic host cell and recovering the protein from the cell or thecell culture supernatant.
 21. A method for treatment of a subjectsuffering from cancer, a chronic infection, or from an inflammatorydisease, comprising the step of administering to the subject apharmaceutical composition comprising an effective amount of the antigenbinding protein of claim 1 or the pharmaceutical composition of claim 3.22. The method of claim 21, wherein the cancer is a solid cancer. 23.The method of claim 21, wherein the cancer is a hematological cancer.24. A method for modulating immune system function in a subject in needthereof, comprising the step of contacting a population of immune cellsof the subject with a pharmaceutical composition comprising an effectiveamount of the antigen binding protein of claim 1, under conditions suchthat the immune system is modulated.
 25. A method for inducing orenhancing an immune response in a subject in need thereof, comprisingthe step of administering to the subject a pharmaceutical compositioncomprising an antigen binding protein, wherein the immune response isgenerated against a tumor antigen.
 26. The method of claim 24 or claim25, wherein the subject is a human subject.
 27. The method of claim 25,wherein the antigen binding protein comprises a bispecific antibody or acomplexing antigen binding protein.
 28. The method of claim 27, whereinthe antigen binding protein, the bispecific antibody, or the complexingantigen binding protein is administered in an amount sufficient toachieve 1, 2, 3, 4, 5, 6, or 7 of the following in the subject: a)reduction of CD39 ATPase activity in a target cell population; b)reduction of regulatory T cells suppression of activity of effector Tcells; c) reduction of levels of regulatory T cells; d) activation ofeffector T cells; e) induction or enhancement of effector T cellproliferation; f) inhibition of tumor growth; and/or g) induction oftumor regression.
 29. The method of claim 28, wherein the target cellpopulation comprises T cells, B cells, monocytes, macrophages, dendriticcells, myeloid-derived suppressor cells, and/or tumor cells.
 30. Themethod of claim 25, wherein the method further comprises one or more ofthe following a) administering chemotherapy; b) administering radiationtherapy; and/or c) administering one or more additional therapeuticagents.
 31. The method of claim 30, wherein the one or more additionaltherapeutic agents comprise one or more immunostimulatory agents. 32.The method of claim 31, wherein the one or more immunostimulatory agentscomprise an antagonist to an inhibitory receptor of an immune cell. 33.The method of claim 32, wherein the inhibitory receptor is at least oneof CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, Tim3, neuritin, BTLA, CECAM-1,CECAM-5, VISTA, LAIR1, CD160, 2B4, TGF-R, and/or a Killer-cellimmunoglobulin-like receptor (KIR).
 34. The method of claim 31, whereinthe one or more immunostimulatory agents comprise an agonist of aco-stimulatory receptor of an immune cell.
 35. The method of claim 34,wherein the co-stimulatory receptor is OX40, CD2, CD27, CDS, ICAM-1,LFA-1, ICOS (CD278), 4-1BB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM,CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or a CD83 ligand. 36.The method of claim 35, wherein the costimulatory receptor or ligandLFA-1 further comprises an LFA-1 β-chains CD18 and/or an LFA-1 α-chainCD11a.
 37. The method of claim 31, wherein the one or moreimmunostimulatory agents comprise a cytokine.
 38. The method of claim37, wherein the cytokine is at least one of IL-2, IL-5, IL-7, IL-12,IL-15, and/or IL-21.
 39. The method of claim 31, wherein the one or moreimmunostimulatory agents comprise an oncolytic virus.
 40. The method ofclaim 39, wherein the oncolytic virus is a Herpes simplex virus, aVesicular stomatitis virus, an adenovirus, a Newcastle disease virus, avaccinia virus, or a maraba virus.
 41. The method of claim 31, whereinthe one or more immunostimulatory agents comprise a chimeric antigenengineered T cell.
 42. The method of claim 31, wherein the one or moreimmunostimulatory agents comprise a bi- or multispecific T cell directedantibody.
 43. The method of claim 25, wherein the one or more additionaltherapeutic agents comprise at least one trap for an immune suppressiveagent.
 44. The method of claim 43, wherein the at least one trap for animmune suppressive agent comprises at least one of an anti-TGF-betaantibody, a TGFb receptor trap, an anti-IL-10 antibody and/or anti-IL-10receptor trap, and/or an anti-IL-35 antibody trap and/or an anti-IL-35receptor trap.
 45. The method of any one of any of claims 3-44, whereinadministration of the pharmaceutical composition results in induction orenhancement of proliferation of a T-effector cell, or modulation ofI-kappaB and/or NF-κB in the T cell, or modulation of CD39 activity inthe T cell, or T cell receptor induced signaling in a T-effector cell,or a combination thereof.
 46. A method of screening for a test compoundcomprising an antigen binding protein of claim 1 capable of inhibitingan activity of CD39, comprising the steps of: contacting a test samplecontaining CD39 with a test compound; comparing the activity of the testsample to a control sample; whereby a decrease in the activity of CD39in the test sample compared to the control sample identifies thecompound as one that inhibits the activity of CD39.
 47. The method ofclaim 46, wherein the control sample comprises a sample not contactedwith a test compound.
 48. An isolated antibody molecule capable ofbinding to human CD39 (hCD39), comprising a heavy chain variable region(VH) and a light chain variable region (VL), VH comprising at least oneof: a) a VHCDR1 having an amino acid sequence that is at least 90%identical to the sequence set forth in SEQ ID NOs: 1-45, b) a VHCDR2having an amino acid sequence that is at least 90% identical to thesequence set forth in SEQ ID NOs: 46-81, and c) a VHCDR3 having an aminoacid sequence that is at least 90% identical to the sequence set forthin SEQ ID NOs: 82-109; and VL comprising at least one of: a) a VLCDR1having an amino acid sequence that is at least 90% identical to thesequence set forth in SEQ ID NOs: 110-124, b) a VLCDR2 having an aminoacid sequence that is at least 90% identical to the sequence set forthin SEQ ID NOs: 125-140, and c) a VLCDR3 having an amino acid sequencethat is at least 90% identical to the sequence set forth in SEQ ID NOs141-166.
 49. An isolated antibody molecule capable of binding to humanCD39 (hCD39), comprising a heavy chain variable region (VH) and a lightchain variable region (VL), VH comprising at least one of: a) a VHCDR1having an amino acid sequence that is homologous to the sequence setforth in SEQ ID NOs: 1-45, b) a VHCDR2 having an amino acid sequencethat is homologous to the sequence set forth in SEQ ID NOs: 46-81, andc) a VHCDR3 having an amino acid sequence that is homologous to thesequence set forth in SEQ ID NOs: 82-109; and VL comprising at least oneof: a) a VLCDR1 having an amino acid sequence that is homologous to thesequence set forth in SEQ ID NOs: 110-124, b) a VLCDR2 having an aminoacid sequence that is homologous to the sequence set forth in SEQ IDNOs: 125-140, and c) a VLCDR3 having an amino acid sequence that ishomologous to the sequence set forth in SEQ ID NOs: 141-166.
 50. Anisolated antibody molecule capable of binding to human CD39 (hCD39),comprising a heavy chain and a light chain, the heavy chain comprisingone or more molecules having a sequence consisting of one of SEQ ID NO:255, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 263, SEQID NO: 265, SEQ ID NO: 267, SEQ ID NO: 269, SEQ ID NO: 271, SEQ ID NO:273, SEQ ID NO: 275, SEQ ID NO: 277, SEQ ID NO: 279, SEQ ID NO: 281, SEQID NO: 283, SEQ ID NO: 285, SEQ ID NO: 287, SEQ ID NO: 289, SEQ ID NO:291, SEQ ID NO: 293, or SEQ ID NO: 295 and the light chain comprisingone or more molecules having a sequence consisting of one of SEQ ID NO:256, SEQ ID NO: 258, SEQ ID NO: 260, SEQ ID NO: 262, SEQ ID NO: 264, SEQID NO: 266, SEQ ID NO: 268, SEQ ID NO: 270, SEQ ID NO: 272, SEQ ID NO:274, SEQ ID NO: 276, SEQ ID NO: 278, SEQ ID NO: 280, SEQ ID NO: 282, SEQID NO: 284, SEQ ID NO: 286, SEQ ID NO: 288, SEQ ID NO: 290, SEQ ID NO:292, SEQ ID NO: 294, or SEQ ID NO:
 296. 51. An isolated antibodymolecule capable of binding to human CD39 (hCD39), comprising a heavychain and a light chain, a) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 255and the light chain comprising one or more, each molecule having asequence consisting of SEQ ID NO: 256; b) the heavy chain comprising oneor more molecules, each molecule having a sequence consisting of SEQ IDNO: 257 and the light chain comprising one or more molecules, eachmolecule having a sequence consisting of SEQ ID NO: 258; c) the heavychain comprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 259 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 260;d) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 261 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 262; e) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 263and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 264; f) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 265 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 266;g) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 267 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 268; h) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 269and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 270; i) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 271 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 272;j) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 273 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 274; k) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 275and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 276; l) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 277 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 278m) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 279 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 280; n) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 281and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 282; o) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 283 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 284;p) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 285 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 286; q) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 287and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 288; r) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 289 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 290;s) the heavy chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 291 and the light chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 292; t) the heavy chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 293and the light chain comprising one or more molecules, each moleculehaving a sequence consisting of SEQ ID NO: 294; or u) the heavy chaincomprising one or more molecules, each molecule having a sequenceconsisting of SEQ ID NO: 295 and the light chain comprising one or moremolecules, each molecule having a sequence consisting of SEQ ID NO: 296.52. An isolated nucleic acid encoding an antigen binding proteinaccording to any one of claims 48-51.
 53. An isolated antibody moleculecapable of binding to human CD39 (hCD39), comprising a heavy chainvariable region (VH) and a light chain variable region (VL), VH and/orVL comprising 1, 2, 3, 4, 5, or 6 of: a) a VHCDR1 sequence comprising:(i) a Kabat CDRH1 sequence defined by the consensus sequence S-Y-Δ₃-M-Δ₅(SEQ ID NOS: 25-29 and 44-45), where Δ₃ is E, F, Q, or Y and Δ₅ is H orY; (ii) a Kabat CDR-H1 sequence defined by the consensus sequenceθ₁-θ₂-θ₃-I-S (SEQ ID NOS: 30-37), where θ₁ is A, H, K, L, S, or W; θ₂ isL, M, N, or T; and θ₃ is A or P; (iii) a Kabat CDR-H1 sequence definedby the consensus sequence η₁-Y-η₃-I-S SEQ ID NOS: 38-41), where η₁ is S,K, N, or R and η₃ is A or G; (iv) a Chothia CDR-H1 sequence defined bythe consensus sequence G-Y-T-F-Ω₅-S-Y (SEQ ID NOS: 1-2 and 4-6), whereΩ₅ is T, K, Q, F, or V; (v) a Chothia CDR-H1 sequence defined by theconsensus sequence G-G-T-F-ν₅-ν₆-Y (SEQ ID NOS: 17-22 and 24), where ν₅is S, G, or E and ν₆ is S, K, R, or S; or (vi) a Chothia CDR-H1consensus sequence defined by the consensus sequence G-G-T-F-κ₅-κ₆-κ₇(SEQ ID NOS: 7-16), where κ₅ is S, Q, P, or A; κ₆ is S, K, H, L, A, orW; and κ₇ is Y, L, T, N, or M, b) a VHCDR2 sequence comprising: (i) aKabat CDR-H2 sequence defined by the consensus sequenceε₁-I-N-P-ε₅-ε₆-G-S-T-ε₁₀-Y-A-Q-K-F-Q-G (SEQ ID NOS: 63-66 and 68), whereε₁ is K, S, R, or V; as is L, R, or S; ε₆ is G or V; and ε₁₀ is S or W;(ii) a Kabat CDR-H2 sequence defined by the consensus sequenceG-I-α₃-α₄-α₅-α₆-G-T-A-N-Y-A-Q-K-F-Q-G (SEQ ID NOS: 69-72), where α₃ is Ior L or is absent; α₄ is P or is absent; and as is I, G, or R; and α₆ isA, F, or G; (iii) a Kabat CDR-H2 sequence defined by the consensussequence β₁-I-I-P-β₅-β₆-G-β₈-A-N-Y-A-Q-K-F-G-Q (SEQ ID NOS: 74 and76-79), where β₁ is S or G; β₅ is I, E, S, or T; β₆ is F, I, or S; andβ₈ is I or T; (iv) a Chothia CDR-H2 sequence defined by the consensussequence N-P-ε₅-ε₆-G-S-T (SEQ ID NOS: 46-48), where ε₅ is L, R, or S andε₆ is G or V; (v) a Chothia CDR-H2 sequence defined by the consensussequence α₃-α₄-α₅-α₆-G-T-A (SEQ ID NOS: 51-54), where α₃ is I or L or isabsent; α₄ is P or is absent; and as is I, G, or R; and α₆ is A, F, orG; or (vi) a Chothia CDR-H2 sequence defined by the consensus sequenceI-P-β₅-β₆-G-β₈-A (SEQ ID NOS: 56-60), where β₅ is I, E, S, or T; β₆ isF, I, or S; and β₈ is I or T, c) a VHCDR3 sequence comprising: (i) aCDR-H3 sequence defined by the consensus sequenceG-K-R-E-G-G-T-E-Y-L-R-γ₁₂ (SEQ ID NOS: 82-86), where γ₁₂ is H, K, S, N,or V; (ii) a CDR-H3 sequence defined by the consensus sequenceE-S-G-Φ₄-Y-R-D-H-R-L-Φ₁₁-V (SEQ ID NOS: 94-96), where Φ₄ is G or T andΦ₁₁ is D or G; or (iii) a CDR-H3 sequence defined by the consensussequence G-G-A-K-Y-A-

₇-

₈-

₉-G-M-D-V (SEQ ID NOS: 87-93), where

₇ is S, V, G, or R;

₈ is T, Q, K, G, or R; and

₉ is Y, H, L, or W, d) a VLCDR1 sequence comprising: (i) a CDR-L1sequence defined by the consensus sequence ϕ₁-A-S-ϕ₄-ϕ₅-V-ϕ₇-ϕ₈-ϕ₉-Y-L-A(SEQ ID NOS: 1101-114), where ϕ₁ is E, K, or R; ϕ₄ is Q or E; ϕ₅ is S orY; ϕ₇ is S or A; ϕ₈ is S or Y; and ϕ₉ is D or S; (ii) a CDR-L1 sequencedefined by the consensus sequence ∂₁-A-S-Q-∂₅-∂₆-∂₇-∂₈-∂₉-L-∂₁₁ (SEQ IDNOS: 118 and 120-123), where ∂₁ is Q or R1; ∂₅ is D or S; ∂₆ is I or V;∂₇ is G or S; ∂₈ is N, R, or S; ∂₉ is N, Y, or W; and ∂₁₁ is A or N; or(iii) a CDR-L1 sequence defined by the consensus sequenceK-S-S-Γ₄-S-V-L-Γ₈-S-Γ₁₀-N-N-K-N-Y-L-A (SEQ ID NOS: 115-117), where Γ₄ isQ, R or K; Γ₈ is F or Y; and Γ₁₀ is S or N, e) a VLCDR2 sequencecomprising: (i) a CDR-L2 sequence defined by the consensus sequenceψ₁-A-S-ψ₄-R-ψ₆-ψ₇ (SEQ ID NOS: 125-136), where ψ₁ is G or Y, ψ₄ is S orN; ψ₆ is A or H; and ψ₇ is T, Y, or N; (ii) a CDR-L2 sequence defined bythe consensus sequence D-A-S-χ₄-R-A-T (SEQ ID NOS: 138 and 139), where£₄ is N or K; or (iii) a CDR-L2 sequence defined by the consensussequence W-A-S-T-R-σ₆-S (SEQ ID NOS: 131 and 133-134), where σ₆ is A, E,or Q, and f) a VLCDR3 sequence comprising: (i) a CDR-L3 sequence definedby the consensus sequence Q-Q-Y-π₄-π₅-π₆-π₇-T (SEQ ID NOS: 141-147),where π₄ is G, H, or Y; π₅ is S, N, F, G, or R; π₆ is S, Y, A, G, or R;and its is P, I, or L; (ii) a CDR-L3 sequence defined by consensussequence Q-Q-λ₃-λ₄-λ₅-λ₆-P-T (SEQ ID NOS: 148-150), where λ₃ is R, F, H,S, L, D, Y, or V; λ₄ is S, V, T, G, L, Y, or N; λ₅ is N, L, F, K, or V;and λ₆ is W, F, Y, or L; (iii) a CDR-L3 sequence defined by theconsensus sequence Q-Q-Y-ρ₃-ρ₄-W-P-L-T (SEQ ID NOS: 151 and 152), whereρ₃ is N or L and ρ₄ is N or L; or (iv) a CDR-L3 sequence defined by theconsensus sequence Q-Q-ω₃-ω₄-ω₅-ω₆-P-ω₅-T (SEQ ID NOS: 153-156), whereω₃ is Y or F; ω₄ is Y or W; ω₅ is S, L, T, or F; ω₆ is T, Y, or F; andω₈ is L or P.